Inhibitors of 11β-hydroxysteroid dehydrogenase type 1

ABSTRACT

This invention relates to novel compounds of the Formulae I or II and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 β-HSD 1 in mammals. Formula (I).

RELATED APPLICATIONS

This application is the U.S. National Phase of PCT/US2009/001215, filedFeb. 26, 2009, which claims the benefit of U.S. Provisional ApplicationNo. 61/031,975, filed Feb. 27, 2008, the entire teachings of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of 11β-hydroxy steroiddehydrogenase type 1 (β-HSD1), pharmaceutical compositions thereof andmethods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormonesthat regulate fat metabolism, function and distribution, and play a rolein carbohydrate, protein and fat metabolism. Glucocorticoids are alsoknown to have physiological effects on development, neurobiology,inflammation, blood pressure, metabolism and programmed cell death.Cortisol and other corticosteroids bind both the glucocorticoid receptor(GR) and the mineralocorticoid receptor (MR), which are members of thenuclear hormone receptor superfamily and have been shown to mediatecortisol function in vivo. These receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Until recently, the major determinants of glucocorticoid action wereattributed to three primary factors: (1) circulating levels ofglucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal(HPA) axis); (2) protein binding of glucocorticoids in circulation; and(3) intracellular receptor density inside target tissues. Recently, afourth determinant of glucocorticoid function has been identified:tissue-specific pre-receptor metabolism by glucocorticoid-activating and-inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD)pre-receptor control enzymes modulate activation of GR and MR byregulation of glucocorticoid hormones. To date, two distinct isozymes of11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as11-beta-HSD type 1, 11betaHSD1, HSD11B1, and HSD11L) and 11β-HSD2.11β-HSD1 is a bi-directional oxidoreductase that regenerates activecortisol from inactive 11-keto forms, whereas 11β-HSD2 is aunidirectional dehydrogenase that inactivates biologically activecortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion,consistent with the differences in their physiological roles. 11β-HSD1is widely distributed in rat and human tissues; expression of the enzymeand corresponding mRNA have been detected in human liver, adiposetissue, lung, testis, bone and ciliary epithelium. In adipose tissue,increased cortisol concentrations stimulate adipocyte differentiationand may play a role in promoting visceral obesity. In the eye, 11β-HSD1may regulate intraocular pressure and may contribute to glaucoma; somedata suggests that inhibition of 11β-HSD1 may cause a drop inintraocular pressure in patients with intraocular hypertension(Kotelevtsev, et al., (1997), Proc. Nat'l Acad. Sci. USA94(26):14924-9). Although 11β-HSD1 catalyzes both11-beta-dehydrogenation and the reverse 11-oxoreduction reaction,11β-HSD1 acts predominantly as a NADPH-dependent oxoreductase in intactcells and tissues, catalyzing the formation of active cortisol frominert cortisone (Low, et al., (1994) J. Mol. Endocrin. 13: 167-174). Incontrast, 11β-HSD2 expression is found mainly in mineralocorticoidtarget tissues such as kidney (cortex and medulla), placenta, sigmoidand rectal colon, salivary gland and colonic epithelial cell lines.11β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing theinactivation of cortisol to cortisone (Albiston, et al., (1994) Mol.Cell. Endocrin. 105: R11-R17), and has been shown to protect the MR fromglucocorticoid excess (e.g., high levels of receptor-active cortisol)(Blum, et al., (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in humanpathology. For example, individuals with mutations in 11β-HSD2 aredeficient in this cortisol-inactivation activity and, as a result,present with a syndrome of apparent mineralocorticoid excess (alsoreferred to as “SAME”) characterized by hypertension, hypokalemia, andsodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, etal., (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205). Similarly,mutations in 11β-HSD1 and in the gene encoding a co-localizedNADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), canresult in cortisone reductase deficiency (CRD); these individualspresent with ACTH-mediated androgen excess (hirsutism, menstrualirregularity, hyperandrogenism), a phenotype resembling polycystic ovarysyndrome (PCOS) (Draper, et al., (2003) Nat. Genet. 34: 434-439).

Notably, disruption of homeostasis in the HPA axis by either deficientor excess secretion or action results in Cushing's syndrome or Addison'sdisease, respectively (Miller & Chrousos, Endocrinology and Metabolism(Felig & Frohman eds., McGraw-Hill: New York, 4^(th) Ed. (2001))387-524). Patients with Cushing's syndrome or receiving glucocorticoidtherapy develop reversible visceral fat obesity. The phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome), thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven,(1993) Ann. Rev. Med. 44, 121-131). Although the role of glucocorticoidsin human obesity is not fully characterized, there is mounting evidencethat 11β-HSD1 activity plays an important role in obesity and metabolicsyndrome (Bujalska, et al., (1997) Lancet 349: 1210-1213); (Livingstone,et al., (2000) Endocrinology 131, 560-563; Rask, et al., (2001) J. Clin.Endocrinol. Metab. 86, 1418-1421; Lindsay, et al., (2003) J. Clin.Endocrinol. Metab. 88: 2738-2744; Wake, et al., (2003) J. Clin.Endocrinol. Metab. 88, 3983-3988).

Data from studies in mouse transgenic models supports the hypothesisthat adipocyte 11β-HSD1 activity plays a central role in visceralobesity and metabolic syndrome (Alberts, et al., (2002) Diabetologia.45(11), 1526-32). Over-expression in adipose tissue of 11β-HSD1 underthe control of the aP2 promoter in transgenic mice produced a phenotyperemarkably similar to human metabolic syndrome (Masuzaki, et al., (2001)Science 294, 2166-2170; Masuzaki, et al., (2003) J. Clinical Invest.112, 83-90). Moreover, the increased activity of 11β-HSD1 in these miceis very similar to that observed in human obesity (Rask, et al., (2001)J. Clin. Endocrinol. Metab. 86, 1418-1421). In addition, data fromstudies with 11β-HSD1-deficient mice produced by homologousrecombination demonstrate that the loss of 11β-HSD1 leads to an increasein insulin sensitivity and glucose tolerance due to a tissue-specificdeficiency in active glucocorticoid levels (Kotelevstev, et al., (1997)Proc. Nat'l Acad. Sci. 94: 14924-14929; Morton, et al., (2001) J. Biol.Chem. 276, 41293-41300; Morton, et al., (2004) Diabetes 53, 931-938).

The published data supports the hypothesis that increased expression of11β-HSD1 contributes to increased local conversion of cortisone tocortisol in adipose tissue and hence that 11β-HSD1 plays a role in thepathogenesis of central obesity and the appearance of the metabolicsyndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17).Therefore, 11β-HSD1 is a promising pharmaceutical target for thetreatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. DrugTargets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore,inhibition of 11β-HSD1 activity may prove beneficial in treatingnumerous glucocorticoid-related disorders. For example, 11β-HSD1inhibitors could be effective in combating obesity and/or other aspectsof the metabolic syndrome cluster, including glucose intolerance,insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia(Kotelevstev, et al., (1997) Proc. Nat'l Acad. Sci. 94, 14924-14929;Morton, et al., (2001) J. Biol. Chem. 276, 41293-41300; Morton, et al.,(2004) Diabetes 53, 931-938). In addition, inhibition of 11β-HSD1activity may have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release (Billaudel & Sutter,(1979) Horm. Metab. Res. 11, 555-560; Ogawa, et al., (1992) J. Clin.Invest. 90, 497-504; Davani, et al., (2000) J. Biol. Chem. 275,34841-34844). Inter-individual differences in general cognitive functionhas been linked to variability in the long-term exposure toglucocorticoids (Lupien, et al., (1998) Nat. Neurosci. 1: 69-73) anddysregulation of the HPA axis. Such chronic exposure to glucocorticoidexcess in certain brain subregions has been theorized to contribute tothe decline of cognitive function (McEwen & Sapolsky (1995) Curr. Opin.Neurobiol. 5, 205-216). Therefore, inhibition of 11β-HSD1 may reduceexposure to glucocorticoids in the brain and thereby protect againstdeleterious glucocorticoid effects on neuronal function, includingcognitive impairment, dementia, and/or depression.

There is also evidence that glucocorticoids and 11β-HSD1 play a role inregulation of in intra-ocular pressure (IOP) (Stokes, et al., (2000)Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz, et al., (2001)Invest. Ophthalmol. Vis. Sci. 42: 2037-2042). If left untreated,elevated IOP can lead to partial visual field loss and eventuallyblindness. Thus, inhibition of 11β-HSD1 in the eye could reduce localglucocorticoid concentrations and IOP, and hence could be used to treator prevent glaucoma and other visual disorders.

Transgenic aP2-11β-HSD1 mice exhibit high arterial blood pressure andhave increased sensitivity to dietary salt. Additionally, plasmaangiotensinogen levels are elevated in the transgenic mice, as areangiotensin II and aldosterone. Treatment of the mice with anangiotensin II antagonist alleviates the hypertension (Masuzaki, et al.,(2003) J. Clinical Invest. 112, 83-90). This suggests that hypertensionmay be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1inhibitors may be useful for treatment of hypertension andhypertension-related cardiovascular disorders.

Glucocorticoids can have adverse effects on skeletal tissues, andprolonged exposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81,3441-3447). In addition, 11β-HSD1 has been shown to be present incultures of human primary osteoblasts as well as cells from adult bone(Cooper, et al., (2000) Bone 27: 375-381), and the 11β-HSD1 inhibitorcarbenoxolone has been shown to attenuate the negative effects ofglucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone23: 119-125). Thus, inhibition of 11β-HSD1 is predicted to decrease thelocal glucocorticoid concentration within osteoblasts and osteoclasts,thereby producing beneficial effects in various forms of bone disease,including osteoporosis.

As evidenced herein, there is a continuing need for new and improveddrugs that inhibit 11β-HSD1. The novel compounds of the presentinvention are effective inhibitors of 11β-HSD1.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic heteroaromatic group or a phenyl group;

R¹ is independently halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹,CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, NR¹¹SO₂R¹³, or HetCy; or a(C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹,C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³;

each R² is independently hydrogen, halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂,C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹,CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹²,OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹²,OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³;

m is an integer from 0-3;

p is 0, 1 or 2;

s is 1 or 2;

t is 1 or 2;

K, L and M are independently selected from O, NR⁴, CR^(4a)R^(4b) or CO;provided: i) that no more than one of K, L and M is CO; ii) that K-L andL-M are not —O—O—; and iii) that K-L-M- is not —O—NR⁴—O— or—NR⁴—NR⁴—NR⁴—;

each R⁴ is independently hydrogen, (C₁-C₆)alkyl, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar orHetAr; or (C₁-C₆)alkyl substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹⁴C(O)NR¹⁴R¹⁵,NR¹⁴C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, NR¹⁴C(O)OR¹⁴, NR¹⁴C(S)OR¹⁴,SO₂R¹⁴, NR¹⁴SO₂R¹⁴, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂NR¹⁴R¹⁵, Ar or HetAr;

each R^(4a) and each R^(4b) is independently selected from hydrogen,OR¹⁴, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(S)R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(S)NHSO₂R¹⁴,OC(O)R¹⁴, OC(S)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴,OC(S)NHSO₂R¹⁴, NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴,SO₂NR¹⁴R¹⁵, NR¹¹SO₂NR¹⁴R¹⁵, Ar, HetAr, or HetCy; or (C₁-C₆)alkyloptionally substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵,NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar, HetAr,or HetCy;

W, X, Y and Z are independently selected from N, CR⁵, provided that nomore than two of W, X, Y and Z are N;

each R⁵ is independently selected from hydrogen, halo, OR¹¹,S(O)_(p)R¹¹, CN, NO₂, COR¹¹, CSR¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹²,NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹²,NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³,NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo,OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³;

each R¹¹ and each R¹² is independently selected from hydrogen,(C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl;

R¹³ is (C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl;

each R¹⁴ and each R¹⁵ is independently hydrogen or (C₁-C₆)alkyl,optionally substituted with OR¹¹, NR¹¹R¹², C(O)R¹¹, C(S)R¹¹, COOR¹¹,C(S)OR¹¹C(O)NR¹¹R¹², C(S)NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(S)R¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², NR¹¹C(O)NHSO₂R¹¹, NR¹¹C(S)NHSO₂R¹¹,OC(O)R¹¹, OC(S)R¹¹, OC(O)NR¹¹R¹², OC(S)NR¹¹R¹², OC(O)NHSO₂R¹¹,OC(S)NHSO₂R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(S)OR¹¹, SO₂R¹¹, NR¹¹SO₂R¹¹,SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², Ar, HetAr, or HetCy;

or NR¹⁴R¹⁵ taken together forms a 4, 5, 6- or 7-membered heterocyclicgroup containing 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1sulfur atoms, said ring being optionally substituted at any one or moresubstitutable ring carbon with oxo, hydroxy, or (C₁-C₃)alkyl, andoptionally substituted at any one or more substitutable ring nitrogenwith (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ or C(O)NR¹¹R¹²;

each Ar is aryl optionally substituted with halogen, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN,CONH₂, (C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy;

each HetAr is heteroaryl optionally substituted with halogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, NO₂, CN, CONH₂, (C₁-C₆)haloakyl or(C₁-C₆)haloalkoxy; and

each HetCy is a monocyclic heterocyclic group containing at least onering atom selected from nitrogen, oxygen or sulfur, said ring beingoptionally substituted at any one or more substitutable ring carbon withoxo, hydroxy, or (C₁-C₃)alkyl, and optionally substituted at any one ormore substitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².

The present invention also provides a pharmaceutical compositioncomprising a disclosed 11β-HSD1 inhibitor, including a compound ofFormula I, and a pharmaceutically acceptable carrier or diluent, whereinthe values for the variables are as described above for the compounds ofFormula I.

The present invention further provides a method of inhibiting 11β-HSD1,comprising administering to a mammal in need thereof an effective amountof a disclosed 11β-HSD1 inhibitor, including a compound of Formula I,wherein the values for the variables are as described above for thecompounds of Formula I.

The present invention further provides a method of inhibiting 11β-HSD1,comprising administering to a mammal in need thereof an effective amountof a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic heteroaromatic group or a phenyl group;

R¹ and each R² is each independently hydrogen, halo, OR¹¹, S(O)_(p)R¹¹,CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³,NR¹¹SO₂R¹³, or HetCy; or a (C₁-C₆)alkyl substituted with halo, OR¹¹,S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³;

Q is CH₂, CH₂CH₂, CH═CH, CH₂O (wherein O is connected to the carbonylcarbon), OCH₂, CH₂NR³ (wherein NR³ is connected to the carbonyl carbon),or NR³CH₂, provided that Q is CH═CH when K is CO and L is NR⁴;

R³ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl;

m is an integer from 0-3;

p is 0, 1 or 2;

s is 1 or 2;

t is 1 or 2;

K, L and M are independently selected from O, NR⁴, CR^(4a)R^(4b) or CO;provided: i) that no more than one of K, L and M is CO; ii) that K-L andL-M are not —O—O—; and iii) that K-L-M- is not —O—NR⁴—O— or—NR⁴—NR⁴—NR⁴—;

each R⁴ is independently hydrogen, (C₁-C₆)alkyl, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar orHetAr; or (C₁-C₆)alkyl substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹⁴C(O)NR¹⁴R¹⁵,NR¹⁴C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, NR¹⁴C(O)OR¹⁴, NR¹⁴C(S)OR¹⁴,SO₂R¹⁴, NR¹⁴SO₂R¹⁴, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂NR¹⁴R¹⁵, Ar or HetAr;

each R^(4a) and each R^(4b) is independently selected from hydrogen,OR¹⁴, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(S)R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(S)NHSO₂R¹⁴,OC(O)R¹⁴, OC(S)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴,OC(S)NHSO₂R¹⁴, NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴,SO₂NR¹⁴R¹⁵, NR¹¹SO₂NR¹⁴R¹⁵, Ar, HetAr, or HetCy; or (C₁-C₆)alkyloptionally substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵,NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar, HetAr,or HetCy;

W, X, Y and Z are independently selected from N, CR⁵, provided that nomore than two of W, X, Y and Z are N;

each R⁵ is independently selected from hydrogen, halo, OR¹¹,S(O)_(p)R¹¹, CN, NO₂, COR¹¹, CSR¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹²,NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹²,NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³,NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo,OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³;

each R¹¹ and R¹² is independently selected from hydrogen, (C₁-C₆)alkylor (C₁-C₆)hydroxyalkyl;

R¹³ is (C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl;

each R¹⁴ and each R¹⁵ is independently hydrogen or (C₁-C₆)alkyl,optionally substituted with OR¹¹, NR¹¹R¹², C(O)R¹¹, C(S)R¹¹, COOR¹¹,C(S)OR¹¹C(O)NR¹¹R¹², C(S)NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(S)R¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², NR¹¹C(O)NHSO₂R¹¹, NR¹¹C(S)NHSO₂R¹¹,OC(O)R¹¹, OC(S)R¹¹, OC(O)NR¹¹R¹², OC(S)NR¹¹R¹², OC(O)NHSO₂R¹¹,OC(S)NHSO₂R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(S)OR¹¹, SO₂R¹¹, NR¹¹SO₂R¹¹,SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², Ar, HetAr, or HetCy;

or NR¹⁴R¹⁵ taken together forms a 4, 5, 6- or 7-membered heterocyclicgroup containing 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1sulfur atoms, said ring being optionally substituted at any one or moresubstitutable ring carbon with oxo, hydroxy, or (C₁-C₃)alkyl, andoptionally substituted at any one or more substitutable ring nitrogenwith (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ or C(O)NR¹¹R¹²;

each Ar is aryl optionally substituted with (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN,(C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy;

each HetAr is heteroaryl optionally substituted with (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN,(C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy; and

each HetCy is a monocyclic heterocyclic group containing at least onering atom selected from nitrogen, oxygen or sulfur, said ring beingoptionally substituted at any one or more substitutable ring carbon withoxo, hydroxy, or (C₁-C₃)alkyl, and optionally substituted at any one ormore substitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².

Also included in the present invention is a method of treating a diseaseor disorder associated with activity or expression of 11β-HSD1,comprising administering to a mammal in need thereof an effective amountof a disclosed 11β-HSD1 inhibitor, including a compound of Formula I orII, or a pharmaceutically acceptable salt thereof.

Also included in the present invention is the use of a disclosed11β-HSD1 inhibitor, including a compound of Formula I or II, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for inhibiting 11β-HSD1 activity in a mammal in need of suchtreatment.

Also included in the present invention is the use of a disclosed11β-HSD1 inhibitor, including a compound of Formula I or II, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating a disease or disorder related to the activity orexpression of 11β-HSD1, inhibiting the conversion of cortisone tocortisol in a cell, inhibiting production of cortisol in a cell,increasing insulin sensitivity in a mammal in need thereof, modulating11β-HSD1 activity in a mammal in need thereof, and/or inhibiting11β-HSD1 in a mammal in need thereof.

Also included in the present invention is a disclosed 11β-HSD1inhibitor, including a compound of Formula I or II, or apharmaceutically acceptable salt thereof, for use in inhibiting 11β-HSD1activity in a mammal in need of such treatment.

Also included in the present invention is a disclosed 11β-HSD1inhibitor, including a compound of Formula I or II, or apharmaceutically acceptable salt thereof, for use in therapy, e.g.,treating a disease or disorder associated with activity or expression of11β-HSD1 in a subject.

Also included in the present invention is a pharmaceutical compositioncomprising a disclosed 11β-HSD1 inhibitor, including a compound ofFormula I or II, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by Structural Formula I or II. Pharmaceutically acceptablesalts of the 11β-HSD1 inhibitors disclosed herein (including thoserepresented by Structural Formulae I or II) are also included in theinvention. Values and alternative values for the variables in StructuralFormulae I and II are provided in the following paragraphs:

A is a monocyclic heteroaromatic group or a phenyl group. Alternatively,A is a phenyl group.

Q is CH₂, CH₂CH₂, CH═CH, CH₂O (wherein O is connected to the carbonylcarbon), OCH₂, CH₂NR³ (wherein NR³ is connected to the carbonyl carbon),or NR³CH₂, provided that Q is CH═CH when K is CO and L is NR⁴.Alternatively, Q is CH═CH.

R¹ is independently halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹,CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, NR¹¹SO₂R¹³ or HetCy; or a(C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹,C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³.

Alternatively, R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, or (C₁-C₃)haloalkoxy.

Each R² is independently hydrogen, halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂,C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹,CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹²,OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹²,OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³.

Alternatively, each R² is independently hydrogen, halo, (C₁-C₃)alkyl,hydroxy, COO(C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy.

R³ is hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl.

Alternatively, R³ is hydrogen or methyl.

m is an integer from 0-3. Alternatively, m=0. Alternatively, m=1.

p is 0, 1 or 2.

s is 1 or 2. Alternatively, s is 1. t is 1 or 2. Alternatively, t is 2.Alternatively, s is 1 and t is 2.

K, L and M are independently selected from O, NR⁴, CR^(4a)R^(4b) or CO;provided: i) that no more than one of K, L and M is CO; ii) that K-L andL-M are not —O—O—; and iii) that K-L-M- is not —O—NR⁴—O— or—NR⁴—NR⁴—NR⁴—.

Each R⁴ is independently hydrogen, (C₁-C₆)alkyl, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar orHetAr; or (C₁-C₆)alkyl substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴,COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹⁴C(O)NR¹⁴R¹⁵,NR¹⁴C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, NR¹⁴C(O)OR¹⁴, NR¹⁴C(S)OR¹⁴,SO₂R¹⁴, NR¹⁴SO₂R¹⁴, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂NR¹⁴R¹⁵, Ar or HetAr.

Alternatively, each R⁴ is independently hydrogen, (C₁-C₆)alkyl, C(O)R¹⁴,COOR¹⁴, or SO₂R¹⁴.

Alternatively, each R⁴ is independently C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴,C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, or SO₂NR¹⁴R¹⁵.

Each R^(4a) and each R^(4b) is independently selected from hydrogen,OR¹⁴, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(S)R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(S)NHSO₂R¹⁴,OC(O)R¹⁴, OC(S)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴,OC(S)NHSO₂R¹⁴, NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴,SO₂NR¹⁴R¹⁵, NR¹¹SO₂NR¹⁴R¹⁵, Ar, HetAr, or HetCy; or (C₁-C₆)alkyloptionally substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, C(O)NHSO₂R¹⁴,C(S)NHSO₂R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵,NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵, OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵,NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar, HetAr,or HetCy.

Alternatively, each R^(4a) and each R^(4b) is independently selectedfrom hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴,NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃).

W, X, Y and Z are independently selected from N, CR⁵, provided that nomore than two of W, X, Y and Z are N. Alternatively, all of W, X, Y andZ are carbon.

each R⁵ is independently selected from hydrogen, halo, OR¹¹,S(O)_(p)R¹¹, CN, NO₂, COR¹¹, CSR¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹²,NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹²,NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³,NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo,OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³;

Alternatively, each R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy.

Each R¹¹ and each R¹² is independently selected from hydrogen,(C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl.

R¹³ is (C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl.

Each R¹⁴ and each R¹⁵ is independently hydrogen or (C₁-C₆)alkyl,optionally substituted with OR¹¹, NR¹¹R¹², C(O)R¹¹, C(S)R¹¹, COOR¹¹,C(S)OR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², NR¹¹C(O)R¹¹, NR¹¹C(S)R¹¹,NR¹¹C(O)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², NR¹¹C(O)NHSO₂R¹¹, NR¹¹C(S)NHSO₂R¹¹,OC(O)R¹¹, OC(S)R¹¹, OC(O)NR¹¹R¹², OC(S)NR¹¹R¹², OC(O)NHSO₂R¹¹,OC(S)NHSO₂R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(S)OR¹¹, SO₂R¹¹, NR¹¹SO₂R¹¹,SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², Ar, HetAr, or HetCy.

Alternatively, NR¹⁴R¹⁵ taken together forms a 4, 5, 6- or 7-memberedheterocyclic group containing 1 or 2 nitrogen atoms, 0 or 1 oxygen atomsand 0 or 1 sulfur atoms, said ring being optionally substituted at anyone or more substitutable ring carbon with oxo, hydroxy, or(C₁-C₃)alkyl, and optionally substituted at any one or moresubstitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².

Each Ar is aryl optionally substituted with halogen, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN,CONH₂, (C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy.

Each HetAr is heteroaryl optionally substituted with halogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, NO₂, CN, CONH₂, (C₁-C₆)haloakyl or(C₁-C₆)haloalkoxy.

Each HetCy is a monocyclic heterocyclic group containing at least onering atom selected from nitrogen, oxygen or sulfur, said ring beingoptionally substituted at any one or more substitutable ring carbon withoxo, hydroxy, or (C₁-C₃)alkyl, and optionally substituted at any one ormore substitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².

In a second embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae III-XX:

Pharmaceutically acceptable salts of the 11β-HSD1 inhibitors disclosedherein (including those represented by any one of Structural FormulaeIII-XX) are also included in the invention. Values and alternativevalues for the variables in Structural Formulae III-XX are as describedabove for Structural Formulae I and II.

In a third embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; and each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a fourth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; and R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a fifth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; and R⁴ is independently C(O)R¹⁴,C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, orSO₂NR¹⁴R¹⁵.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a sixth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴; and each R^(4a) and each R⁴¹)is independently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵,NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃).

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a seventh embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently C(O)R¹⁴,C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, orSO₂NR¹⁴R¹⁵; and each R^(4a) and each R^(4b) is independently selectedfrom hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴,NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃).

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In an eighth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴; each R^(4a) and each R^(4b) isindependently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵,NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); and R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a ninth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently C(O)R¹⁴,C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, orSO₂NR¹⁴R¹⁵; each R^(4a) and each R^(4b) is independently selected fromhydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴, HetCy,(C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted with NR¹⁴R¹⁵, COOR¹⁴,C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) and each R^(4b) isindependently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂, CH₂C(O)NHSO₂CH₃,NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); and R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a tenth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴; each R^(4a) and each R^(4b) isindependently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵,NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy; andR¹⁴ is hydrogen and R¹⁵ is independently hydrogen, (C₁-C₃)alkyl,hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, (C₁-C₃)alkylamino(C₁-C₃)alkyl,or di-(C₁-C₃)alkylamino(C₁-C₃)alkyl.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In an eleventh embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴; each R^(4a) and each R^(4b) isindependently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵,NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵,OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted withNR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) andeach R^(4b) is independently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂,CH₂C(O)NHSO₂CH₃, NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy; andNR¹⁴R¹⁵ taken together forms a 5- or 6-membered heterocyclic groupcontaining 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfuratoms, said ring being optionally substituted at any one or moresubstitutable ring carbon with oxo, hydroxy, or (C₁-C₃)alkyl, andoptionally substituted at any one or more substitutable ring nitrogenwith (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ or C(O)NR¹¹R¹².

Values and alternative values for the remainder of the variables inStructural is Formulae I-XX are as described for Structural Formulae Iand II.

In a twelfth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently C(O)R¹⁴,C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, orSO₂NR¹⁴R¹⁵; each R^(4a) and each R^(4b) is independently selected fromhydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴, HetCy,(C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted with NR¹⁴R¹⁵, COOR¹⁴,C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) and each R^(4b) isindependently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂, CH₂C(O)NHSO₂CH₃,NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy; andR¹⁴ is hydrogen and R¹⁵ is independently hydrogen, (C₁-C₃)alkyl,hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, (C₁-C₃)alkylamino(C₁-C₃)alkyl,or di-(C₁-C₃)alkylamino(C₁-C₃)alkyl.

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

In a thirteenth embodiment, the 11β-HSD1 inhibitors of the invention arerepresented by a structural formula selected from any one of StructuralFormulae I-XX, wherein the values for each of the variables in thestructural formulae are defined below:

R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy; each R² is independently hydrogen, halo,(C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl, COO(C₁-C₃)alkyl, CONH₂,(C₁-C₃)alkoxy, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy; R⁴ is independently C(O)R¹⁴,C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, orSO₂NR¹⁴R¹⁵; each R^(4a) and each R^(41i) is independently selected fromhydrogen, OR¹⁴, NR¹⁴R¹⁵, C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴,NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴, OC(O)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴, HetCy,(C₁-C₃)alkyl, or (C₁-C₃)alkyl substituted with NR¹⁴R¹⁵, COOR¹⁴,C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵ (e.g., each R^(4a) and each R^(4b) isindependently hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂, CH₂C(O)NHSO₂CH₃,NH₂, NHCH₃, N(CH₃)2,

NHCH₂COOH, NHC(O)CH₃, NHC(O)CH₂CH₂COOH, NHC(O)NHSO₂CH₃, OH, OCH₂COOH,OCH₂COOCH₂CH₃,

OC(O)CH₃, OC(O)CH₂NH₂, OC(O)CH₂CH₂COOH, OC(O)N(CH₃)₂,

or OC(O)NHSO₂CH₃); R⁵ is independently hydrogen, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂,C(O)NH(C₁-C₃)alkyl, C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy; andNR¹⁴R¹⁵ taken together forms a 5- or 6-membered heterocyclic groupcontaining 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfuratoms, said ring being optionally substituted at any one or moresubstitutable ring carbon with oxo, hydroxy, or (C₁-C₃)alkyl, andoptionally substituted at any one or more substitutable ring nitrogenwith (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ or C(O)NR¹¹R¹².

Values and alternative values for the remainder of the variables inStructural Formulae I-XX are as described for Structural Formulae I andII.

Specific 11β-HSD1 inhibitors of the invention and pharmaceuticallyacceptable salts thereof are provided in Examples 1-105 and PropheticExamples 1-34 below.

Specific examples of compounds of Formulae I-XX may exist in variousstereoisomeric or tautomeric forms. The invention encompasses all suchforms, including active compounds in the form of essentially pureenantiomers, racemic mixtures, and tautomers, including forms those notdepicted structurally.

When any variable (e.g., aryl, heterocyclyl, R¹, R², etc.) occurs morethan once in a compound, its definition on each occurrence isindependent of any other occurrence.

The term “alkyl”, used alone or as part of a larger moiety such as“alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, “alkylamine”, “dialkyamine”,“alkoxycarbonyl” or “alkylaminocarbonyl”, means a saturated straight orbranched hydrocarbon radical having (unless otherwise specified) 1-10carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “cycloalkyl” means a saturated hydrocarbon ring having 3-8carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “aryl” means a 6-10 membered carbocyclic aromatic monocyclic orpolycyclic ring system, such as phenyl or naphthyl. The term “aryl” maybe used interchangeably with the terms “aryl ring” “aromatic ring”,“aryl group” and “aromatic group”.

“Heteroaromatic group”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, means a 5-10 membered monovalentmonocyclic and polycyclic aromatic group radical containing 1 to 4heteroatoms independently selected from N, O, and S. Heteroaryl groupsinclude furyl, thienyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridinyl-N-oxide, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl,benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl,4H-quinolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzothienyl,benzofuranyl, 2,3-dihydrobenzofuranyl, benzodioxolyl, benzimidazolyl,indazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, cinnolinyl,phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl,1,2,5-thiadiazolyl-1-oxide, 1,2,5-thiadiazolyl-1,1-dioxide,1,3,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, andpteridinyl. The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”,“heteroaryl group” and “heteroaromatic group” are used interchangeablyherein.

The term “heterocyclic group” means a 4-, 5-, 6- and 7-memberedsaturated or partially unsaturated heterocyclic ring containing 1 to 4heteroatoms independently selected from N, O, and S, and includepyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran,tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane,1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane,morpholine, thiomorpholine, thiomorpholine 1,1-dioxide,tetrahydro-2H-1,2-thiazine 1,1-dioxide, and isothiazolidine 1,1-dioxide.The terms “heterocyclyl”, “heterocycle”, “heterocyclic group” and“heterocyclic ring” are used interchangeably herein.

The term “ring atom” is an atom such as C, N, O or S that is in the ringof an aryl group, heteroaryl group, cycloalkyl group or heterocyclicgroup. A “substitutable ring atom” in an aryl, heteroaryl cycloalkyl orheterocyclic is a carbon or nitrogen atom in the aryl, heteroaryl,cycloalkyl or heterocyclic group that is bonded to at least one hydrogenatom. The hydrogen(s) can be optionally replaced with a suitablesubstituent group. Thus, the term “substitutable ring atom” does notinclude ring carbon or nitrogen atoms when the structure depicts thatthey are not attached to any hydrogen atoms. For example, the carbonatom in the phenyl ring that is attached to the double bond inStructural Formulas (III)-(XX) is not a substitutable ring carbon atom.

Suitable substituents for an alkyl, aryl, heteroaryl and heterocyclicgroup are those which do not significantly reduce the ability of thecompound to inhibit the activity of 11β-HSD1. Unless otherwisespecified, suitable substituents for an alkyl, aryl, heteroaryl andheterocyclyl include halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹,CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a(C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹,C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³, wherein R¹¹⁻¹³are as described above. Preferred substituents an alkyl, aryl,heteroaryl and heterocyclyl include, unless otherwise specified,halogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, NO₂, CN, CONH₂, (C₁-C₆)haloakyl or(C₁-C₆)haloalkoxy.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,and triethiodide salts.

The compounds of the invention include pharmaceutically acceptableanionic salt forms, wherein the anionic salts include the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,and triethiodide salts.

Salts of the disclosed 11β-HSD1 inhibitors containing an acidicfunctional group can be prepared by reacting with a suitable base. Sucha pharmaceutically acceptable salt may be made with a base which affordsa pharmaceutically acceptable cation, which includes alkali metal salts(especially sodium and potassium), alkaline earth metal salts(especially calcium and magnesium), aluminum salts and ammonium salts,as well as salts made from physiologically acceptable organic bases suchas trimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine, collidine, quinine, quinoline, and basic amino acidssuch as lysine and arginine.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that solvates orhydrates of the compound or its pharmaceutically acceptable salts areincluded as well as anhydrous forms of the compound and forms withoutsolvent. “Solvates” refer to crystalline forms wherein solvent moleculesare incorporated into the crystal lattice during crystallization.Solvate may include water or nonaqueous solvents such as ethanol,isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates,wherein water is the solvent molecule incorporated into the crystallattice, are typically referred to as “hydrates”. Hydrates includestoichiometric hydrates as well as compositions containing variableamounts of water.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that thecompound, including solvates thereof, may exist in crystalline forms,non-crystalline forms or a mixture thereof. The compound or itspharmaceutically acceptable salts or solvates may also exhibitpolymorphism (i.e. the capacity to occur in different crystallineforms). These different crystalline forms are typically known as“polymorphs.” It is to be understood that when named or depicted bystructure, the disclosed compound and its pharmaceutically acceptablesalts, solvates or hydrates also include all polymorphs thereof.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. One of ordinary skill inthe art will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used in solidifying thecompound. For example, changes in temperature, pressure, or solvent mayresult in different polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The invention also includes various isomers and mixtures thereof“Isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers).

Certain of the disclosed 11β-HSD1 inhibitors may exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Enantiomers are pairs of stereoisomers whosemirror images are not superimposable, most commonly because they containan asymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. The symbol“*” in a structural formula represents the presence of a chiral carboncenter. “R” and “S” represent the configuration of substituents aroundone or more chiral carbon atoms. Thus, “R*” and “S*” denote the relativeconfigurations of substituents around one or more chiral carbon atoms.When a chiral center is not defined as R or S, a mixture of bothconfigurations is present.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration.

Many of the disclosed 11β-HSD-1 inhibitors have a double bond(s). Whenthe bonding of a group to the double bond is represented with a

the configuration about the double bond can be Z, E or a mixturethereof.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has at least one chiralcenter, it is to be understood that the name or structure encompassesone enantiomer of inhibitor free from the corresponding optical isomer,a racemic mixture of the inhibitor and mixtures enriched in oneenantiomer relative to its corresponding optical isomer.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 95%, 98%, 99% or 99.9% by weight pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 95%, 98%, 99% or 99.9% by weight optically pure. Percent opticalpurity by weight is the ratio of the weight of the enantiomer over theweight of the enantiomer plus the weight of its optical isomer. When asingle geometric isomer, e.g., a geometric isomer with a double bond, isdepicted by name or structure and the stereochemistry about the doubleis indicated, the compound is considered to be at least 60%, 70%, 80%,90%, 95%, 98%, 99% or 99.9% stereochemically pure by weight. Percentstereochemically purity by weight is the ratio of the weight of thegeometric isomer over the weight of the both geometric isomers. Forexample, 99% stereochemically pure means that at least 99% by weight ofthe compound is the indicated stereoisomer.

A pharmaceutical composition of the invention may, alternatively or inaddition to a compound of Formulae I-XX, comprise a pharmaceuticallyacceptable salt of a compound of Formulae I-XX, or a prodrug orpharmaceutically active metabolite of such a compound or salt and one ormore pharmaceutically acceptable carriers therefor.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. Such responseincludes alleviation of the symptoms of the disease or disorder beingtreated. The effective amount of a compound of the invention in such atherapeutic method is from about 0.01 mg/kg/day to about 10 mg/kg/day,preferably from about 0.5 mg/kg/day to 5 mg/kg/day.

“Inhibiting 11β-HSD1” means to decrease the activity of the 11β-HSD1enzyme.

“Modulating 11β-HSD1” means to impact the activity of the 11β-HSD1enzyme by altering its natural activity. Modulation can be analogous toinhibition when a disease or disorder relating to the activity 11β-HSD1would be effectively treated by suppressing the activity of the enzyme.

“Pharmaceutically acceptable carrier” means compounds and compositionsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention and that, when appropriately administeredto an animal or human, do not produce an adverse reaction.

“Treatment” or “treating”, as used herein, includes prophylactic andtherapeutic treatment. “Therapeutic treatment” includes partially ortotally inhibiting, delaying, or reducing the severity of the disease ordisorder related to 11β-HSD1. “Prophylactic treatment” encompassesadministration of a compound of the invention to a subject susceptibleto a disease or disorder related to the activity or expression of11β-HSD1 in an effort to reduce the likelihood of a subject developingthe disease or disorder, or slowing or preventing progression of thedisease. Prophylactic treatment includes suppression (partially orcompletely) of the disease or disorder, and further includes reducingthe severity of the disease or disorder, if onset occurs. Prophylactictreatment is particularly advantageous for administration to mammals atrisk for developing a disease or disorder related to 11β-HSD1.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Additionally, thecompounds of the present invention can be administered intranasally ortransdermally.

It will be obvious to those skilled in the art that the following dosageforms may comprise as the active ingredient, either compounds or acorresponding pharmaceutically acceptable salt of a compound of thepresent invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can either besolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersable granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier is a finely dividedsolid which is in a mixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from about one to aboutseventy percent of the active ingredient. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Tablets, powders, cachets, lozenges, fast-melt strips, capsules andpills can be used as solid dosage forms containing the active ingredientsuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activeingredient is dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example, water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared bydissolving the active ingredient in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired. Aqueoussuspensions for oral administration can be prepared by dispersing thefinely divided active ingredient in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. Insuch form, the composition is subdivided into unit doses containingappropriate quantities of the active ingredient. The unit dosage formcan be a packaged preparation, the package containing discretequantities of, for example, tablets, powders, and capsules in vials orampules. Also, the unit dosage form can be a tablet, cachet, capsule, orlozenge itself, or it can be the appropriate amount of any of these inpackaged form.

The quantity of active ingredient in a unit dose preparation may bevaried or adjusted from about 0.1 mg to about 1000.0 mg, preferably fromabout 0.1 mg to about 100 mg. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill inthe art. Also, the pharmaceutical composition may contain, if desired,other compatible therapeutic agents.

In therapeutic treatment or as a method-of-use as an inhibitor of11β-HSD1 or an inhibitor in the production of cortisol in the cell, theactive ingredient is preferably administered orally in a solid dosageform as disclosed above in an amount of about 0.1 mg to about 100 mg perdaily dose where the dose is administered once or more than once daily.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus, obesity, metabolic syndrome, insulin resistance,cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy,osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety andAlzheimer's disease, cognitive decline (including age-related cognitivedecline), polycystic ovarian syndrome and infertility. In addition,compounds modulate the function of B and T cells of the immune system.

A pharmaceutical composition of the invention may, alternatively or inaddition to a compound of Formulae I-XX, comprise a pharmaceuticallyacceptable salt of a compound of Formulae I-XX, or a prodrug orpharmaceutically active metabolite of such a compound or salt and one ormore pharmaceutically acceptable carriers therefor.

The invention includes a therapeutic method for treating or amelioratingan 11β-HSD1 mediated disorder in a mammal in need thereof comprisingadministering to a subject in need thereof an effective amount of acompound of Formulae I-XX, or the enantiomers, diastereomers, or saltsthereof or composition thereof.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus, obesity, symptoms of metabolic syndrome, glucose intolerance,hyperglycemia, hypertension, hyperlipidemia, insulin resistance,cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy,osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceralfat obesity associated with glucocorticoid therapy, depression, anxiety,Alzheimer's disease, dementia, cognitive decline (including age-relatedcognitive decline), polycystic ovarian syndrome, infertility andhypergonadism. In addition, the compounds modulate the function of B andT cells of the immune system and can therefore be used to treat diseasessuch as tuberculosis, leprosy and psoriasis. They can also be used topromote wound healing, particularly in diabetic patients.

Additional diseases or disorders that are related to 11β-HSD1 activityinclude those selected from the group consisting of lipid disorders,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,diabetes, coronary heart disease, stroke, peripheral vascular disease,Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X.

The term “mammal” is preferably a human, but can also be an animal inneed of veterinary treatment, e.g., companion animals (e.g., dogs, cats,and the like), farm animals (e.g., cows, sheep, pigs, horses, and thelike) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

The disclosed 11β-HSD1 inhibitors can be used alone or in a combinationtherapy with one or more additional agents for the treatment ofdiabetes, dyslipidemia, cardiovascular disease, hypertension, obesity,cancer or glaucoma. Agents for the treatment of diabetes includeinsulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis),Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, suchas Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazonehydrochloride, Takeda/Eli Lilly); sulfonylureas, such as Amaryl®(glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis),Micronase®/Glynase® (glyburide, Pfizer), and Glucotrol®/Glucotrol XL®(glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm®(repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), andGlufast® (mitiglinide, Takeda); biguanides, such asGlucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) andGlumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs;GLP-1 analogs; DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck);PTB-1B inhibitors; protein kinase inhibitors (including AMP-activatedprotein kinase inhibitors); glucagon antagonists; glycogen synthasekinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogenphosphorylase inhibitors; sodium glucose co-transporter inhibitors, andα-glucosidase inhibitors, such as Precose®/Glucobay®/Prandase®/Glucor®(acarbose, Bayer) and Glyset® (miglitol, Pfizer). Agents for thetreatment of dyslipidemia and cardiovascular disease include statins,fibrates and ezetimibe. Agents for the treatment of hypertension includeα-blockers, β-blockers, calcium channel blockers, diuretics, angiotensinconverting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase(NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosteronesynthase inhibitor, aldosterone-receptor antagonists, or endothelinreceptor antagonist. Agents for the treatment of obesity includeorlistat, phentermine, sibutramine and rimonabant.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of any one of Structural Formulae I-XX orcomposition thereof in a combination therapy with one or more other11β-HSD1 inhibitors (whether such inhibitors are also compounds of anyone of Structural Formulae I or are compounds of a differentclass/genus), or with combination products, such as Avandamet®(metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepirideand rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl,Bristol Myers Squibb); Janumet® (sitagliptin and metformin, Merck) andGlucovance® (glyburide and metformin HCl, Bristol Myers Squibb).

The following abbreviations have the indicated meanings:

Abbreviation Meaning Boc tert-butoxy carbonyl or t-butoxy carbonyl(Boc)₂O di-tert-butyl dicarbonate BOP(Benzotriazole-1-yl-oxy-tris-(dimethylamino)- phosphoniumhexafluorophosphate) Cbz Benzyloxycarbonyl CbzCl Benzyl chloroformateDAST diethylaminosulfur trifluoride DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexylcarbodiimide DCUN,N′-dicyclohexylurea DIAD diisopropyl azodicarboxylate DIEAN,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMFN,N-dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP2,4-dinitrophenylhydrazine DPTBS Diphenyl-t-butylsilyl EDC,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide EDC•HCl, hydrochlorideEDCI Equiv equivalents Fmoc 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-Fmoc-OSu 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedioneh, hr hour(s) HOBt 1-hydroxybenzotriazole HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateKHMDS potassium hexamethyldisilazane LAH or LiAlH₄ lithium aluminumhydride LC-MS liquid chromatography-mass spectroscopy LHMDS lithiumhexamethyldisilazane Me methyl MsCl methanesulfonyl chloride Min minuteMS mass spectrum NaH sodium hydride NaHCO₃ sodium bicarbonate NaN₃sodium azide NaOH sodium hydroxide Na₂SO₄ sodium sulfate NMMN-methylmorpholine NMP N-methylpyrrolidinone Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether Quantquantitative yield Satd saturated SOCl₂ thionyl chloride SFCsupercritical fluid chromatography SPA scintillation proximity assay SPEsolid phase extraction TBAF tetrabutylammonium fluoride TBSt-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TBSClt-butyldimethylsilyl chloride TBDPSCl t-butyldiphenylsilyl chloride TEAtriethylamine or Et₃N TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy freeradical Teoc 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5- dione TFAtrifluoroacetic acid Tlc, TLC thin layer chromatography TMStrimethylsilyl TMSCl chlorotrimethylsilane or trimethylsilyl chloridet_(R) retention time TsOH p-toluenesulfonic acid

General Description of Synthetic Methods

Compounds of Formulae I or II can be prepared by several processes. Inthe discussion below, R¹, R², R³, R⁴, R^(4a), R^(4b), R⁵, K, L, M, W, X,Y, Z, m, n and p have the meanings indicated above unless otherwisenoted. In cases where the synthetic intermediates and final products ofFormulae I or II described below contain potentially reactive functionalgroups, for example amino, hydroxyl, thiol and carboxylic acid groups,that may interfere with the desired reaction, it may be advantageous toemploy protected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. (T. W. Greene and P. G. M. Wuts “ProtectiveGroups in Organic Synthesis” John Wiley & Sons, Inc., New York 1999).Such protecting group manipulations are assumed in the discussion belowand not described explicitly. Generally, reagents in the reactionschemes are used in equimolar amounts; however, in certain cases it maybe desirable to use an excess of one reagent to drive a reaction tocompletion. This is especially the case when the excess reagent can bereadily removed by evaporation or extraction. Bases employed toneutralize HCl in reaction mixtures are generally used in slight tosubstantial excess (1.05-5 equivalents).

In a first process, a compound of Formula XXI, can be prepared byreaction of a cinnamic acid derivative of Formula XXII, wherein R^(a) isa leaving group such as chloride, 1-imidazolyl, methanesulfonyloxy or1-succinimidyloxy, with a spirocyclic amine of Formula XXIII.Alternatively a cinnamic acid of Formula XXII, wherein R^(a) is OH, maybe activated in situ by use of a peptide coupling reagent such as EDCIin the presence of HOBt, HATU, HBTU or BOP

Many cinnamic acids of Formula XXII can be purchased. Cinnamic acids ofFormula XXII, wherein R^(a) is OH, can be prepared by reaction ofbenzaldehydes of Formula XXIV and malonic acid (Formula XXV) underKnoevenagel conditions.

Cinnamic esters of Formula XXII, wherein R^(a) is lower alkoxy, can beprepared by reaction of bromo or iodobenzenes of Formula XXVI, whereinX=Br or I respectively, with acrylate esters of Formula XXVII, whereinR^(a) is lower alkoxy, in the presence of a palladium catalyst underHeck reaction conditions.

Many spirocyclic amines of Formula XXIII can be prepared by previouslydescribed routes or can be purchased.

The following substituted(±)-2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid werepurchased from WuXi Pharmatech (Shanghai, China) as their N-Boc or ethylester derivatives:

The two enantiomers of tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylatewere also obtained from WuXi Pharmatech (Shanghai, China).

(±)-2-(2,3-Dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid can beprepared by deprotection of2-(1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid as disclosed in Example 98 (Steps A and B) of U.S. Pat. No.5,578,593, which is hereby incorporated by reference. It, and thefollowing substituted analogs, can also be purchased from WuXiPharmatech (Shanghai, China).

tert-Butyl7-bromo-3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylatewas purchased from WuXi Pharmatech (Shanghai, China):

tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate waspurchased from WuXi Pharmatech (Shanghai, China):

6-Methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] wasprepared as disclosed in Procedure A in U.S. Pat. No. 7,109,207 (Column25, Line 5), which is hereby incorporated by reference.

1′-(tert-butoxycarbonyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carboxylicacid was purchased from WuXi Pharmatech (Shanghai, China).

1′-tert-butyl 5-methyl2-oxospiro[indoline-3,4′-piperidine]-1′,5-dicarboxylate was purchasedfrom WuXi Pharmatech (Shanghai, China).

tert-Butyl 5-fluoro-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylatewas prepared as disclosed in U.S. Pat. No. 7,279,486 Example 6 Step 1),which is hereby incorporated by reference.

tert-Butyl spiro[indoline-3,4′-piperidine]-1-carboxylate (Formula XXIIwherein K, L, Y=C; X=N; R¹, K, L and R² form a fused benzene ring; n=0;s=1; t=2; R⁴=CO₂t-Bu; R⁵=H; R³ absent; single bonds from L to X and X toY):

can be prepared from benzylspiro[indoline-3,4′-piperidine]-1′-carboxylate as disclosed in Example21 of U.S. Pat. No. 7,045,527, which is hereby incorporated byreference.

The following substituted tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate can be purchased from WuXiPharmatech (Shanghai, China):

2,3-Dihydrospiro[indene-1,4′-piperidine] can be prepared from indeneusing the procedures disclosed by Chambers, M. S., et al., J. Med. Chem.1992, 35, 2033-2039, Scheme II, and can be purchased from WuXiPharmatech (Shanghai, China).

(±)-2,3-Dihydrospiro[indene-1,4′-piperidine]-3-carboxylic acid can beprepared by deprotection of1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylicacid which can be prepared from tert-butyl3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate asdisclosed in Example 1 (Steps A-D) of U.S. Pat. No. 5,965,565, which ishereby incorporated by reference. This compound was purchased from WuXiPharmatech (Shanghai, China).

3H-spiro[isobenzofuran-1,4′-piperidine] can be prepared as described inCheng, C. Y., et al., Tetrahedron 1996, 52, 10935.3H-spiro[isobenzofuran-1,4′-piperidine] can also be purchased from J & WPharmLab LLC (Morrisville, Pa., USA).

2H-spiro[benzofuran-3,4′-piperidine] can be prepared as described inParham, W. E., et al., J. Org. Chem. 1976, 41, 2628.

3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] can be purchased fromWuXi Pharmatech (Shanghai, China):

Spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one can be prepared asdescribed in Clark, R. D. et al J. Med. Chem. 1983, 26, 657, which ishereby incorporated by reference.

1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one can be prepared asdescribed in US Patent application 2005/215576 pages 19 and 20, which ishereby incorporated by reference.

Spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one can be preparedas described in WO 2006/041830 pp 53-55, which is hereby incorporated byreference.

In a second process, a compound of Formula I can be prepared fromanother compound of Formula I. For example:

(1) A compound of Formula I, wherein R² is bromine or iodine, can beconverted to a compound of Formula I wherein R² is cyano by reactionwith Cu(I)CN or with Zn(CN)₂ in the presence of a palladium catalyst.

(2) A compound of Formula I, wherein R² is bromine or iodine, can beconverted to a compound of Formula I wherein R² is (C₁-C₆)alkoxycarbonylby reaction with carbon monoxide and a (C₁-C₆)alkyl alcohol in thepresence of a palladium catalyst.

(3) A compound of Formula I, wherein R² is (C₁-C₆)alkoxycarbonyl, can beconverted to a compound of Formula I wherein R² is CONH₂ by reactionwith an alkali metal hydroxide to give a compound of Formula I, whereinR² is CO₂H, followed by coupling with ammonia using EDC in the presenceof HOBt.(4) A compound of Formula I, wherein R² is (C₁-C₆)alkoxycarbonyl, can beconverted to a compound of Formula I wherein R² is CH₂OH by treatmentwith a reducing agent such as LiBH₄.(5) A compound of Formula I, wherein R² is (C₁-C₆)alkoxycarbonyl, can beconverted to a compound of Formula I wherein R² is C(Me₂)OH by reactionwith at least 2 equivalents of methylmagnesium halide or methyl lithium.(6) A compound of Formula I wherein K is C═O, L is NH and M is a singlebond can be converted to a compound of Formula I, wherein K is C═O, L isNR⁴, M is a single bond and R⁴ is (C₁-C₆)alkyl, by treatment with a basesuch as NaH and a (C₁-C₆)alkyl halide in a solvent such as THF or DMF.(7) A compound of Formula I, wherein R^(4a) is CH₂CO₂H, can be convertedto a compound of Formula I, wherein R^(4a) is CH₂CONHMe or CH₂CONMe₂, byreaction with methylamine or dimethylamine respectively and a peptidecoupling reagent such as EDC, DIC or HATU.(8) A compound of Formula I, wherein R^(4a) is CO₂H or CH₂CO₂H, can bereduced to a compound of Formula I, wherein R^(4a) is CH₂OH or CH₂CH₂OHby reduction with borane in THF.(9) A compound of Formula I, wherein R^(4a) is CO₂Me or CH₂CO₂Me, can beconverted to a compound of Formula I, wherein R^(4a) is CMe₂OH orCH₂CMe₂OH, by reaction with at least 2 equivalents of methylmagnesiumhalide or methyllithium.(10) A compound of Formula I, wherein R^(4a) is OH, can be converted toa compound of Formula I, wherein R^(4a) is chloride, by reaction withthionyl chloride, followed by treatment with a cyclic amine suchN-methylpiperazine or morpholine, to give a compound of Formula I,wherein R^(4a) is 1-methyl-4-piperazino or 4-morpholino.(11) A compound of Formula I, wherein R^(4a) is NH₂ can be converted toa compound of Formula I wherein R^(4a) is NMe₂ by treatment withformaldehyde and formic acid under Eschweiler-Clark conditions.(12) A compound of Formula I, wherein R^(4a) is OH can be converted to acompound of Formula I, wherein R^(4a) is

by reaction with carbonyl diimidazole followed by morpholine.(13) A compound of Formula I, wherein K is CH₂, L is CO and M is asingle bond, can be converted to a compound of Formula I, wherein K isCH₂, L is CR^(4a)R^(4b), M is a single bond, R^(4a) is OH and R^(4b) isMe, by reaction with methylmagnesium halide or methyllithium.(14) A compound of Formula I, wherein R^(4a) is CO₂H or CH₂CO₂H, can beconverted to a compound of Formula I, wherein R^(4a) is C(═O)NHSO₂Me orCH₂C(═O)NHSO₃Me by treatment with methanesulfonamide and EDC.(15) A compound of Formula I, wherein R^(4a) is CH₂CO₂H, can beconverted to a compound of Formula I, wherein R^(4a) is CH₂NH₂ bytreatment with diphenylphosphoryl azide followed by water.(16) A compound of Formula I, wherein R^(4a) is CH₂NH₂ can be convertedto a compound of Formula I wherein R^(4a) is CH₂NMe₂ by treatment withformaldehyde and formic acid under Eschweiler-Clark conditions.(17) A compound of Formula I, wherein R^(4a) is OH can be converted to acompound of Formula I, wherein R^(4a) is OC(═O)NMe₂, by reaction withcarbonyl diimidazole followed by dimethylamine.(18) A compound of Formula I, wherein R^(4a) is OH can be converted to acompound of Formula I, wherein R^(4a) is OC(═O)NHSO₂Me, by reaction withcarbonyl diimidazole followed by methanesulfonamide.(19) A compound of Formula I, wherein R^(4a) is CH₂NH₂ can be convertedto a compound of Formula I, wherein R^(4a) is CH₂NHMe, by sequentialreaction with (i) di-tert-butyldicarbonate (ii) NaH, MeI and (iii) TFA,CH₂Cl₂.(20) A compound of Formula I, wherein R^(4a) is OH can be converted to acompound of Formula I, wherein R^(4a) is

by reaction with NaH and 4-(2-chloroethyl)morpholine.(21) A compound of Formula I, wherein R^(4a) is CH₂CO₂H can be convertedto a compound of Formula I, wherein R^(4a) is

by sequential reaction with (i) tert-butyl piperazine-1-carboxylate inthe presence of EDC or HATU and 4-(2-chloroethyl)morpholine and (ii) TFAin CH₂Cl₂.(22) A compound of Formula I, wherein R^(4a) is OH can be converted to acompound of Formula I, wherein R^(4a) is

by reaction with NaH and 1-(2-chloroethyl)-4-methylpiperazine.(23) A compound of Formula I, wherein K is CH₂, L is CO and M is asingle bond, can be converted to a compound of Formula I, wherein K isCH₂, L is CO and M is NH, by treatment with hydroxylamine to give acompound of Formula I, wherein K is CH₂, L is C═NOH and M is a singlebond, followed by treatment with a strong acid under Beckmannrearrangement conditions.(24) A compound of Formula I, wherein X is CR⁵ and R⁵ is Br or I, can beconverted to a compound of Formula I wherein X is CR⁵ and R⁵ is(C₁-C₆)alkoxycarbonyl by reaction with carbon monoxide and a(C₁-C₆)alkyl alcohol in the presence of a palladium catalyst.(25) A compound of Formula I, wherein X is CR⁵ and R⁵ is(C₁-C₆)alkoxycarbonyl-C, can be converted to a compound of Formula Iwherein X is CR⁵ and R⁵ is CONH₂ by reaction with an alkali metalhydroxide to give a compound of Formula I, wherein X is CR⁵ and R⁵ isCO₂H, followed by coupling with ammonia using EDC in the presence ofHOBt.(26) A compound of Formula I, wherein X is CR⁵ and R⁵ is(C₁-C₆)alkoxycarbonyl, can be converted to a compound of Formula Iwherein X is CR⁵ and R⁵ is CH₂OH by treatment with a reducing agent suchas LiBH₄.(27) A compound of Formula I, wherein X is CR⁵ and R⁵ is(C₁-C₆)alkoxycarbonyl, can be converted to a compound of Formula Iwherein X is CR⁵ and R⁵ is C(Me₂)OH by reaction with at least 2equivalents of methylmagnesium halide or methyl lithium.

LC-MS Methods

Method 1 [LC-MS (3 min)]

Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10Method 2 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0   90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nmOven Temp 50° C. MS ESI ionizationMethod 3 (30-90)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0   70 30 2.2 10 90 2.5 10 90 Flow Rate 1 mL/min Wavelength UV220 OvenTemp 50° C. MS ESI ionization

Intermediate Preparations Preparation 17-bromospiro[isoindoline-1,4′-piperidin]-3-one

Step 1

A mixture of tert-butyl-4-oxopiperidine-1-carboxylate (19 g, 0.0.096mol), 4-methoxybenzylamine (13 g, 0.096 mol) and toluene was stirred at100° C. for 3 h and then concentrated to give a residue. Toluene (300mL), 3-bromo-2-iodo-benzoyl chloride (25 g, 0.077 mol), and Et₃N (24.5g, 0.23 mol) were added to the residue and the mixture was stirred at80° C. overnight. The mixture was cooled, and poured into water andextracted with EtOAc. The organic layer was dried and concentrated togive the crude product which was purified by column chromatography toafford tert-butyl4-(3-bromo-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate(30 g, 63%). ¹H NMR: (400 MHz, MeOD): δ=1.38 (s, 9H), 1.43 (m, 2H), 1.48(m, 4H), 1.63 (m, 2H), 3.18 (m, 2H), 3.60 (m, 2H), 3.80 (s, 3H), 4.55(d, 1H), 5.49 (m, 1H), 6.88 (m, 3H), 7.02 (m, 2H), 7.16 (m, 1H), 7.32(m, 3H), 7.55 (m, 1H).

Step 2

A solution of tert-butyl4-(3-bromo-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate(30 g, 0.048 mol) in CH₃CN (500 mL) was stirred for 0.5 h undernitrogen. K₂CO₃ (13 g, 0.096 mol), PPh₃ (6 g, 20%), tetra-butylammoniumchloride (15 g, 0.048 mol) and Pd(OAc)₂ (3 g, 0.0048 mol) were added.The resulting mixture was heated to reflux for 12 h. The mixture waspoured into water and extracted with EtOAc. The organic layer was driedand concentrated to give the crude product which was purified by columnchromatography to afford tert-butyl7-bromo-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate(12 g, 50%). ¹H NMR: (400 MHz, CDCl₃): δ=1.51 (s, 9H), 1.73 (m, 2H),2.83-3.08 (m, 2H), 3.79 (s, 3H), 4.00 (m, 1H), 4.30 (m, 1H), 4.42 (d,1H), 5.02 (d, 1H), 6.83 (d, 2H), 7.201 (d, 2H), 7.45 (m, 1H), 7.70 (d,1H), 7.88 (d, 1H).

Step 3

A solution of tert-butyl7-bromo-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate(5 g, 0.01 mol) in TFA (50 mL) and CF₃SO₃H (5 mL) was stirred and heatedfor 8 h. The mixture was concentrated to give a residue which was washedwith aq NaOH and extracted with EtOAc. The organic layer was dried andconcentrated to give7-bromo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (2.0 g,72%).

Step 4

A solution of7-bromo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (2 g,0.0072 mol) in CH₃COOH was hydrogenated in the presence of PtO₂ for 1.5h. The catalyst was removed by filtration and the filtrate wasconcentrated to give the crude product which was washed with saturatedaq Na₂CO₃. The solvent was removed to give the7-bromospiro[isoindoline-1,4′-piperidin]-3-one (2 g, 100%).

2-methylspiro[isoindoline-1,4′-piperidin]-3-one was prepared followingprocedures analogous to those described above using methylamine and2-iodobenzoyl chloride in Step 1 and omitting Step 3.

7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one was preparedfollowing procedures analogous to those described above usingmethylamine and 3-chloro-2-iodobenzoyl chloride in Step 1 and omittingStep 3.

7-chlorospiro[isoindoline-1,4′-piperidin]-3-one was prepared followingprocedures analogous to those described above using3-chloro-2-iodobenzoyl chloride in Step 1.

Preparation 2 3,5-dichloro-2-iodobenzoyl chloride

Step 1

To a solution of 3,5-dichloro-benzoic acid (25 g, 0.13 mol) in 125 mL ofconcentrated H₂SO₄ at 0° C. was added HNO₃ (68%) dropwise. The mixturewas stirred at 0° C. and allowed to warm to rt overnight. The mixturewas poured into ice-water. The suspension was then filtered and thesolid was washed with cold water and dried to give the crude product (30g, 98%). ¹H NMR (d₆-DMSO): 8.01 (s, 1H), 8.28 (s, 1H).

Step 2

H₂ was sent to a solution of 3,5-dichloro-2-nitrobenzoic acid (20 g,0.085 mol), Re—Ni (2.0 g) in MeOH (400 mL). The mixture was stirred atrt overnight. The mixture was filtered and concentrated to give thecrude product (17 g, 98%). ¹H NMR (d₆-DMSO): 7.27 (s, 2H), 7.66 (m, 2H).

Step 3

A solution of 2-amino-3,5-dichloro-benzoic acid (17 g, 0.083 mol), NaNO₂(6.29 g, 0.09 mol) and NaOH (5 M, 17 mL) in 150 mL of water was addedslowly to a stirred and cooled solution of HCl (36%, 31 mL) in 120 mL ofwater (0-5° C.). The formed solution was stirred at that temperature for30 min, and then added to a solution of KI (21 g, 0.125 mol) and H₂SO₄(98%, 7 mL) in 40 mL of water. The mixture was slowly heated to 50° C.for 30 min, which was then raised to 100° C. to remove iodine. After 2h, the mixture was cooled, treated with Na₂S₂O₄ (1.2 g, 0.006 mol) andallowed to stand overnight. The mixture was filtered and the solid waswashed with cooled water, dried to give the crude product (21.5 g, 82%).¹H NMR (d₆-DMSO): 7.53 (s, 1H), 7.82 (m, 1H).

Step 4

A mixture of 3,5-dichloro-2-iodo-benzoic acid (9.0 g, 28 mmol) and SOCl₂(100 mL) was heated to reflux overnight. The solvent was removed to givecrude 3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 98%). ¹H NMR (CDCl₃):7.64 (m, 2H).

Preparation 3 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one

Step 1

A 500-mL flask was charged with 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (7.0 g, 35 mmol), 4-methoxy-benzylamine (4.8 g, 35mmol) and 120 mL of toluene. The mixture was heated to reflux for 12 h.The yellow-orange solution was allowed to cool to ambient and thenevaporated. The residue was used directly in the next step withoutfurther purification. It was dissolved in 150 mL of toluene. Then3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 28 mmol) and Et₃N (4.5 g, 44mmol) was added. The mixture was heated to reflux overnight. The mixturewas acidified with 0.5 N aq HCl, and the layers were separated. Theorganic layer was washed with brine, dried and concentrated to give thecrude product. It was purified by column chromatography (PE:EtOAc=15:1)to give the desired product (9.0 g, 42%).

Step 2

4-[(3,5-Dichloro-2-iodo-benzoyl)-(4-methoxy-benzyl)-amino]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (9.0 g, 15 mmol) was dissolved in 100 mL ofacetonitrile in a three flask fitted with a condenser and the mixturewas sparged with N₂ for 1 h. The flask was quickly opened and Pd(OAc)₂(336 mg, 1.5 mmol), PPh₃ (786 mg, 3.0 mmol), K₂CO₃ (4.14 g, 30 mmol) and^(n)Bu₄NBr (4.82 g, 15 mmol) was added. The mixture was heated to refluxovernight. After this time, the iodide was consumed and the mixture wascooled to rt and evaporated. The residue was taken up with EtOAc/H₂O andthe layers were separated. The organic layer was washed with brine,dried and concentrated to give the crude product. It was purified bycolumn chromatography (PE:EtOAc=10:1) to give tert-butyl5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate(3.5 g, 48%). ¹H NMR (CDCl₃): 1.52 (s, 9H), 1.63 (s, 1H), 1.78 (m, 1H),2.71 (m, 1H), 3.04 (m, 1H), 3.78 (s, 3H), 3.97 (m, 1H), 4.25 (m, 1H),4.46 (m, 1H), 5.02 (m, 1H), 6.82 (m, 2H), 7.18 (m, 2H), 7.52 (s, 1H),7.81 (s, 1H).

Step 3

tert-Butyl5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate(3.5 g, 7.2 mmol) in TFA (36 mL) and CF₃SO₃H (4 mL) was heated to 60° C.for 5 h. The solvent was removed and satd aq NaHCO₃ was added till pH=7.Then EtOAc was added, the organic layer was washed with brine, dried andconcentrated to give the crude product. It was purified by preparativeHPLC to give5,7-dichloro-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one(0.2 g, 10%). ¹H NMR (CDCl₃): 1.66 (m, 3H), 2.81 (m, 1H), 3.15 (m, 1H),3.76 (m, 1H), 7.57 (m, 1H), 7.75 (m, 1H).

Step 4

H₂ was sent to the solution of5,7-dichloro-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one(400 mg, 1.5 mmol), PtO₂ (40 mg) in acetic acid (10 mL). The mixture wasstirred at rt for 2 h. The mixture was filtered, the filtrate wasneutralized with satd aq NaHCO₃ and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried and concentratedto give 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one (300 mg,73%). ¹H NMR (CD₃OD): 1.36 (m, 2H), 2.76 (m, 2H), 2.94 (m, 2H), 3.12 (m,2H), 7.67 (m, 2H).

Preparation 4 2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one

Step 1

A mixture of 1-benzyl-4-piperidone (8.5 g, 45 mmol), phenylacetamide(6.1 g, 45 mmol) and polyphosphoric acid (˜100 g) was heated at 100° C.for 2 d. Water (100 mL) was added and the mixture was allowed to cool tort. The mixture was diluted and made strongly basic by addition of NaOHpellets and water (900 mL). The mixture was extracted with CH₂Cl₂ (3×200mL). The combined organic extracts were washed with brine andconcentrated to leave a red solid (14.16 g). Three recrystallizationfrom i-PrOH (40 mL) afforded1′-benzyl-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one (2.79 g, 20%)as a white solid. LC-MS Method 1 t_(R)=0.92 min, m/z=307.

Step 2

A solution of 1′-benzyl-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one(2.79 g, 9.1 mmol) in 4:1 EtOAc/HOAc (100 mL) was added to 10% Pd on C.The mixture was shaken under 50 psi of H₂ at rt for 3 h. The mixture wasfiltered through Celite and the filtrate was concentrated to give awhite solid (2.60 g). This material was dissolved in MeOH (80 mL) andCH₂Cl₂ (80 mL). Amberlyst A26 OH⁻ (12 g) was added. The mixture wasstirred for 0.5 h and filtered. The filtrate was concentrated to afford2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one (1.59 g, 80%) as a whitesolid. LC-MS Method 1 t_(R)=0.58 min, m/z=217.

Preparation 51,1-dimethyl-1H-spiro[isoquinoline-4,4′-piperidin]-3(2H)-one

Polyphosphoric acid (10 g) was heated to 140° C. and4-cyano-4-phenylpiperidine (1.00 g, 5.4 mmol) was added. The mixture wasstirred for 2 min under a reflux condenser and acetone (2 mL, 27 mmol)was added through the condenser. The mixture was stirred at 140° C. for1 h and poured onto crushed ice. After the ice had melted, the mixturewas basified by addition of solid K₂CO₃. The mixture was extracted withCH₂Cl₂ (2×100 mL). The combined CH₂Cl₂ extracts were washed with brine,dried over Na₂SO₄ and concentrated to afford an amber oil (1.19 g). Thismaterial was dissolved in 5% aq HCl (50 mL) and washed with ether (2×50mL). The aq HCl layer was basified with solid K₂CO₃ and extracted withCH₂Cl₂ (2×50 mL). These CH₂Cl₂ extracts were dried over Na₂SO₄ andconcentrated to furnish crude1,1-dimethyl-1H-spiro[isoquinoline-4,4′-piperidin]-3(2H)-one (0.32 g,24%) as a brown oil. LC-MS Method 1 t_(R)=0.40 min, m/z=245.

Example 1 (±)-(E)-ethyl2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

A solution of (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate TFAsalt (31 mg, 0.07 mmol) in CH₂Cl₂ was treated with MP-carbonate resin(2.89 mmol g⁻¹, 200 mg, 0.58 mmol). The mixture was stirred for 0.5 hand filtered. To the filtrate were added ortho-(trifluoromethyl)cinnamicacid (42 mg, 0.19 mmol), i-Pr₂NEt (0.07 mL, 0.39 mmol) and solid HATU(37 mg, 0.10 mmol). The mixture was stirred at rt for 4 h. A 10-mLChem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed tostand for 5 min. The reaction mixture was applied and the cartridge waseluted with ether (20 mL). The eluate was passed through a second 10-mLChem-Elut cartridge that had been prewetted with satd aq NaHCO₃ (6 mL).The eluate was evaporated and the residue was purified by preparativeHPLC to afford (±)-(E)-ethyl2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(15 mg, 42%) as an oil. LC-MS Method 1 t_(R)=2.23, min, m/z=550, 552; ¹HNMR (CDCl₃) 1.28 (t, 3H), 1.40-1.80 (3H), 2.43 (m, 2H), 2.76 (m, 1H),2.91 (m, 2H), 3.18 (m, 1H), 3.34 (m, 1H), 3.62 (m, 1H), 4.14 (m, 1H),4.19 (q, 2H), 4.80 (m, 1H), 6.83 (d, 1H), 7.11 (m, 2H), 7.35-7.75 (5H),7.92 (m, 1H).

Example 2(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

(±)-(E)-ethyl2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(13 mg, mmol) was dissolved in THF (0.4 mL) and MeOH (0.8 mL). Asolution of LiOH.H₂O (10 mg) in water (0.4 mL) was added. The mixturewas stirred at rt for 5 d. The reaction mixture was submitted directlyto preparative HPLC to afford(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (6 mg, %) as a solid. LC-MS Method 1 t_(R)=1.92, min, m/z=522, 524.

Example 2 Isomer 1(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 1

Step 1

To a solution of tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylateisomer 1 (200 mg, 0.44 mmol) in anhydrous CH₂Cl₂ (2 mL) was added 20%TFA in CH₂Cl₂ (10 mL) at 0° C. The reaction mixture was stirred at rtfor 1 h. The reaction mixture was concentrated to give ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer1 as its trifluoroacetate salt (156 mg, 100%), which was used to thenext step without purification.

Step 2

To a solution of ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer1 (156 mg, 0.44 mmol) in anhydrous CH₂Cl₂ (6 mL) was added(E)-3-(2-(trifluoromethyl)phenyl)acrylic acid (96 mg, 0.44 mmol), HOBt(120 mg, 0.89), EDCI (175 mg, 0.89) and i-Pr₂NEt (286 mg, 2.22 mol) at0° C. and then stirred overnight under N₂. Then the reaction mixture waswashed with 1 N aq HCl and water. The organic phase was dried overNa₂SO₄, filtered and concentrated to afford a residue, which waspurified by TLC to give(E)-ethyl2-(7-bromo-F-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (172 mg, 71%). ¹H NMR (CD₃OD): 1.25 (m, 3H), 1.47 (m, 2H), 1.50(s, 1H), 1.71 (m, 1H), 2.48 (m, 2H), 2.74 (m, 1H), 2.90 (m, 2H), 3.15(m, 1H), 3.33 (m, 1H), 3.61 (m, 1H), 4.10 (m, 1H), 4.19 (m, 2H), 4.79(m, 1H), 6.82 (m, 1H), 7.05 (m, 2H), 7.42 (m, 2H), 7.53 (m, 1H), 7.68(m, 2H), 7.95 (m, 1H). 443-071-3

Step 3

To the solution of(E)-ethyl2-(7-bromo-F-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (172 mg, 0.31 mmol) in methanol (5 mL) was added 2 M aqLiOH.H₂O at rt and the mixture was stirred for 8 h. The reaction mixturewas concentrated to remove methanol and extracted with CH₂Cl₂ (2×). Thecombined organic phases were dried, filtered and concentrated to give(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 1 (106 mg, 65%). ¹H NMR (CD₃OD): 1.58 (m, 2H), 1.82 (m, 1H),2.48 (m, 2H), 2.74-3.06 (m, 3H), 3.15 (m, 1H), 3.43 (m, 1H), 3.61 (m,1H), 4.32 (m, 1H), 4.70 (m, 1H), 7.10 (m, 1H), 7.24 (m, 2H), 7.36 (m,1H), 7.56 (m, 1H), 7.66 (m, 1H), 7.78 (m, 1H), 7.96 (m, 1H).

Example 2 Isomer 2(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 2

The title compound was prepared following a procedure analogous to thatdescribed for Example 2 Isomer 1 using tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylateisomer 2 in Step 1. ¹H NMR: (400 MHz, CD₃OD): δ=0.84 (m, 1H), 1.18 (m,2H), 1.46 (m, 2H), 1.73 (m, 1H), 2.41 (m, 2H), 2.74 (m, 1H), 2.85 (m,1H), 3.08 (m, 1H), 3.31 (m, 1H), 3.57 (m, 1H), 4.26 (m, 1H), 4.63 (m,1H), 7.05 (m, 1H), 7.17 (m, 2H), 7.33 (m, 1H), 7.48 (m, 1H), 7.60 (m,1H), 7.69 (m, 1H), 7.89 (m, 2H).

Example 3(±)-(E)-2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that described in Example 2. LC-MSMethod 1 t_(R)=1.9, min, m/z=478, 480; ¹H NMR (CDCl₃) 1.20-1.40 (3H),1.72 (m, 1H), 2.40 (m, 1H), 2.51 (m, 1H), 2.65-3.40 (5H), 3.62 (m, 1H),4.10 (d, 1H), 4.78 (d, 1H), 6.84 (d, 1H), 7.05-7.2 (3H), 7.46 (m, 1H),7.58 (m, 1H), 7.66 (m, 2H), 7.95 (d, 1H).

Example 4(±)-(E)-2-(7-chloro-1′-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and4-fluoro-2-(trifluoromethyl)cinnamic acid followed by a procedureanalogous to that described in Example 2. LC-MS Method 1 t_(R)=1.95,min, m/z=496, 498; ¹H NMR (CDCl₃) 1.20-1.40 (3H), 1.70 (m, 1H), 2.40 (m,1H), 2.53 (m, 1H), 2.65-3.05 (4H), 3.30 (m, 1H), 3.62 (m, 1H), 4.06 (d,1H), 4.79 (d, 1H), 6.80 (d, 1H), 7.1-7.5 (5H), 7.68 (m, 1H), 7.85 (d,1H).

Example 5(±)-(E)-2-(7-chloro-1′-(3-(5-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and5-fluoro-2-(trifluoromethyl)cinnamic acid followed by a procedureanalogous to that described in Example 2. LC-MS Method 1 t_(R)=1.93,min, m/z=496, 498; ¹H NMR (CDCl₃) 1.20-1.40 (3H), 1.70 (m, 1H), 2.39 (m,1H), 2.51 (m, 1H), 2.65-3.05 (4H), 3.36 (m, 1H), 3.62 (br s, 1H), 4.06(d, 1H), 4.79 (d, 1H), 6.83 (d, 1H), 7.0-7.5 (5H), 7.70 (m, 1H), 7.87(d, 1H).

Example 6(±)-(E)-2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetamide

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that described in Example 2. LC-MSMethod 1 t_(R)=1.9, min, m/z=478; ¹H NMR (CDCl₃) 1.38 (d, 1H), 1.42 (d,1H), 1.51 (m, 1H), 2.38 (m, 2H), 2.7-3.5 (m, 6H), 4.10 (d, 1H), 4.79 (d,1H), 5.5 (br s, 2H), 6.84 (d, 1H), 7.05-7.20 (3H), 7.43 (m, 1H), 7.57(m, 1H), 7.68 (m, 2H), 7.94 (d, 1H).

Example 7(±)-(E)-2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-N-methyl-N-(2-(methylamino)ethyl)acetamide

A vial was charged with(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (5 mg, 0.01 mmol), N,N′-dimethylethylenediamine (0.007 mL, 0.066mmol), HOBt (3 mg, 0.02 mmol), i-Pr₂NEt (0.006 mL, 0.032 mmol) andCH₂Cl₂ (1 mL). EDC.HCl (4 mg, 0.021 mmol) was added. The mixture wasstirred at rt for 1 d and evaporated to dryness. The residue waspurified by preparative HPLC to afford(±)-(E)-2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-N-methyl-N-(2-(methylamino)ethyl)acetamide(1.0 mg, 14%). LC-MS Method 1 t_(R)=1.55, min, m/z=548, 550.

Example 8(±)-(E)-2-(7-chloro-1′-(3-(2-chlorophenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and2,3-dichlorocinnamic acid followed by a procedure analogous to thatdescribed in Example 2. LC-MS Method 1 t_(R)=1.88, min, m/z=444, 446,448; ¹H NMR (CDCl₃) 1.40 (dd, 1H), 1.52 (d, 2H), 1.74 (m, 1H), 2.39 (m,1H), 2.48 (m, 1H), 2.6-3.2 (4H), 3.30 (m, 1H), 3.62 (m, 1H), 4.11 (d,1H), 4.80 (d, 1H), 6.92 (d, 1H), 7.05-7.30 (5H), 7.41 (m, 1H), 7.62 (m,1H), 8.00 (d, 1H).

Example 9(±)-(E)-2-(7-chloro-1′-(3-(2,3-dichlorophenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and2,3-dichlorocinnamic acid followed by a procedure analogous to thatdescribed in Example 2. LC-MS Method 1 t_(R)=1.98, min, m/z=480; ¹H NMR(CDCl₃) 1.52 (d, 2H), 1.71 (m, 2H), 2.40 (m, 1H), 2.49 (m, 1H),2.65-3.10 (4H), 3.32 (m, 1H), 3.62 (m, 1H), 4.13 (d, 1H), 4.79 d, 1H),6.88 (d, 1H), 7.05-7.30 (4H), 7.46 (d, 1H), 7.52 (d, 1H), 8.00 (d, 1H).

Example 10(±)-(E)-2-(6-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that described in Example 2. LC-MSMethod 1 t_(R)=1.92, min, m/z=458; ¹H NMR (CDCl₃) 1.63 (4H), 2.11 (m,1H), 2.36 (s, 3H), 2.47 (m, 1H), 2.70 (m, 1H), 2.85-3.05 (m, 3H), 3.38(m, 1H), 3.61 (br s, 1H), 4.10 (m, 1H), 4.76 (m, 1H), 6.84 (m, 1H), 6.98(s, 1H), 7.05 (m, 2H), 7.44 (m, 1H), 7.58 (m, 1H), 7.67 (m, 2H), 7.97(d, 1H).

Example 11(±)-(E)-2-(6-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(6-fluoro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that described in Example 2. LC-MSMethod 1 t_(R)=, min, m/z=; ¹H NMR (CDCl₃) 1.63 (4H), 2.06 (m, 1H), 2.49(m, 1H), 2.72 (m, 1H), 2.80-3.00 (3H), 3.38 (m, 1H), 3.62 (br s, 1H),4.09 (m, 1H), 4.75 (m, 1H), 6.80-7.00 (3H), 7.16 (m, 1H), 7.43 (m, 1H),7.58 (m, 1H), 7.63 (m, 2H), 7.98 (d, 1H).

Example 12(±)-(E)-2-(5-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared employing a procedure analogous to thatdescribed in Example 1 using methyl2-(5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that described in Example 2. ¹H NMR(CDCl₃) 1.61 (4H), 2.10 (m, 1H), 2.32 (s, 3H), 2.47 (m, 1H), 2.70 (m,1H), 2.85-3.05 (3H), 2.37 (m, 1H), 3.62 (br s, 1H), 4.06 (m, 1H), 4.73(m, 1H), 6.83 (m, 1H), 7.02 (s, 1H), 7.08 (s, 2H), 7.43 (m, 1H), 7.57(m, 1H), 7.80 (m, 2H), 7.98 (d, 1H)

Example 13(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetamide

To a solution of(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid isomer 1 (100 mg, 0.19mmol) in anhydrous CH₂Cl₂ (4 mL) were added HOBt (52 mg, 0.38 mmol),EDCI (76 mg, 0.38 mmol) and i-Pr₂NEt (123 mg, 0.95 mmol) in an ice waterbath. The mixture was stirred overnight under NH₃ at rt. The reactionmixture was washed with 1 N aq HCl and the aqueous phase was extractedwith CH₂Cl₂ (2×). The combined organic phases were dried, filtered andconcentrated to give a residue, which was purified by preparative TLC toafford(±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetamideisomer 1 (52 mg, 53%). ¹H NMR (CD₃OD): 1.52 (m, 2H), 1.82 (m, 1H), 4.01(m, 1H), 2.35 (m, 1H), 2.76 (m, 2H), 3.08 (m, 2H), 3.41 (m, 1H), 3.62(m, 1H), 4.31 (m, 1H), 4.62 (m, 1H), 4.71 (m, 1H), 7.12 (m, 1H), 7.22(m, 2H), 7.38 (m, 1H), 7.53 (m, 1H), 7.66 (m, 1H), 7.72 (m, 1H), 7.98(m, 2H).

Example 14(±)-(E)-2-(6-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 7 using 0.5 M NH₃ in dioxane and(±)-(E)-2-(6-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid. LC-MS Method 1 t_(R)=1.67, min, m/z=461.

Example 15(E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indene-1,4′-piperidin]-3(2H)-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using7-bromospiro[indene-1,4′-piperidin]-3(2H)-one. LC-MS Method 1t_(R)=1.92, min, m/z=478, 480; ¹H NMR (CDCl₃) 1.45 (m, 2H), 2.78 (m,3H), 3.03 (m, 2H), 3.29 (m, 1H), 4.22 (m, 1H), 4.91 (m, 1H), 6.83 (d,1H), 7.20-8.00 (8H).

Example 16(±)-(E)-1-(7-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

To a stirred solution of(E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indene-1,4′-piperidin]-3(2H)-one(20 mg, 0.042 mmol) in MeOH (2 mL) and THF (2 mL) was added solid NaBH₄(12 mg). The mixture was stirred at rt for 3 h. The mixture was dilutedwith 10% aq citric acid and extracted with ether (2×30 mL). The combinedether extracts were dried over MgSO₄ and concentrated. The residue waspurified by prep HPLC to afford(±)-(E)-1-(7-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one(1.8 mg, 9%) as a solid. LC-MS Method 1 t_(R)=1.83, min, m/z=480, 482;¹H NMR (CDCl₃) 1.39 (m, 2H), 1.63 (m, 1H), 2.12 (m, 1H), 2.5-3.0 (4H),3.36 (m, 1H), 4.16 (m, 1H), 4.82 (m, 1H), 5.23 (br s, 1H), 6.86 (d, 1H),7.18 (m, 1H), 7.3-7.8 (6H), 7.95 (d, 1H).

Example 17(E)-7-bromo-1′-(3-(2,6-dichlorophenyl)acryloyl)spiro[indene-1,4′-piperidin]-3(2H)-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 15 using 2,6-dichlorocinnamic acid. LC-MS Method 1t_(R)=1.95, min, m/z=478, 480, 482; ¹H NMR (CDCl₃) 1.45 (2H), 2.7-2.9(3H), 3.00 (m, 2H), 3.29 (m, 1H), 4.20 (m, 1H), 4.92 (m, 1H), 6.6-8.0(8H).

Example 18(±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

Step 1

To a stirred solution of tert-butyl7-bromo-3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(196 mg, 0.52 mmol) in MeOH (20 mL) were added NH₄OAc (795 mg, 10.3mmol) and NaCNBH₃ (324 mg, 5.2 mmol). The mixture was heated at refluxfor 1 d. The mixture was concentrated under reduced pressure, dilutedwith EtOAc (90 mL), washed with 1M aq NaOH (25 mL) and dried overNa₂SO₄. Removal of the solvent gave crude (±)-tert-butyl3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(264 mg) which was used without purification.

Step 2

To a stirred solution of crude (±)-tert-butyl3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(264 mg, 0.69 mmol) in THF (5 mL) was added 10% aq K₂CO₃ (10 mL),followed by Teoc-OSu (269 mg, 1.04 mmol). The mixture was stirred at rtfor 3 d, diluted with ether (80 mL), washed with brine (25 mL) and driedover MgSO₄. Removal of the solvent left an oil (240 mg) which waspurified chromatography on a 12-g silica cartridge, eluted with a 0-50%EtOAc in hexanes gradient to afford (±)-tert-butyl7-bromo-3-((2-(trimethylsilyl)ethoxy)carbonylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(85 mg, 31% for 2 steps). LC-MS Method 1 t_(R)=2.35 min, m/z=425, 427,547, 549.

Step 3

A solution of (±)-tert-butyl7-bromo-3-((2-(trimethylsilyl)ethoxy)carbonylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(85 mg, 0.16 mmol) and TsOH.H₂O (32 mg, 0.17 mmol) in EtOH (2 mL) andEt₂O (30 mL) was placed under vacuum on a rotary evaporator and thewater bath was warmed from rt to 60° C. The mixture was held undervacuum at 60° C. for 1 h. The solid residue was dissolved in CH₂Cl₂ (100mL), washed with satd aq NaHCO₃ (10 mL) and dried over Na₂SO₄. Removalof the solvent left (±)-2-(trimethylsilyl)ethyl7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (56 mg,81%) as an oil. LC-MS Method 1 t_(R)=1.50 min, m/z=425, 427.

Step 4

To a stirred solution of (±)-2-(trimethylsilyl)ethyl7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (23 mg,0.056 mmol), ortho-(trifluoromethyl)cinnamic acid (16 mg, 0.074 mmol)and i-Pr₂NEt (0.027 mL, 0.15 mmol) in CH₂Cl₂ (3 mL) was added solid HATU(28 mg, 0.0.074 mmol). The mixture was stirred overnight at rt andevaporated to leave a residue which was purified by preparative HPLC toafford (±)-(E)-2-(trimethylsilyl)ethyl7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate(16.5 mg, 47%). LC-MS Method 1 t_(R)=2.37 min, m/z=623, 625.

Step 5

(±)-(E)-2-(trimethylsilyl)ethyl7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate(16.5 mg, 0.026 mmol) and Et₄NF (30 mg) were dissolved in MeCN (3 mL).The solution was heated at 100° C. for 10 min in a microwave. Thesolution was concentrated and the residue was purified by preparativeHPLC to give(±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one(11 mg, 70%) as its TFA salt. LC-MS Method 1 t_(R)=1.38, min, m/z=479,481; ¹H NMR (CD₃OD) 1.53 (m, 1H), 1.67 (m, 1H), 2.08 (m, 1H), 2.55 (m,1H), 2.9-3.5 (5H), 4.38 (d, 1H), 4.72 (d, 1H), 7.2-8.0 (9H).

Example 19(±)-(E)-1-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-3-methylurea

A vial equipped with a flea stirbar was charged with(±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-oneTFA salt (9 mg, 0.015 mmol), i-Pr₂NEt (0.01 mL) and CH₂Cl₂ (1 mL). MeNCO(0.05 mL, 0.085 mmol) was added. The mixture was stirred at rt for 3 hand evaporated to dryness. The residue was purified by prep HPLC toafford(±)-(E)-1-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-3-methylurea(2.9 mg, 59%). LC-MS Method 1 t_(R)=1.77, min, m/z=536, 538.

Example 20 (E)-tert-butyl1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using tert-butyl1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate. LC-MS Method 1t_(R)=2.18, min, m/z=501; ¹H NMR (CDCl₃) 1.48 (s, 9H), 1.60-2.20 (4H),3.05 (m, 1H), 3.40-4.20 (4H), 4.50-4.80 (3H), 6.85 (d, 1H), 7.12 (m,1H), 7.20 (m, 2H), 7.35 (m, 1H), 7.44 (m, 1H), 7.58 (m, 1H), 7.69 (m,2H), 7.99 (m, 1H).

Example 21(E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

To a stirred solution of (E)-tert-butyl1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate(64 mg, 0.13 mmol) in CH₂Cl₂ (2 mL) was added 4 M HCl in dioxane (2 mL).The mixture was stirred at rt for 2 h and concentrated to afford(E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-oneas its hydrochloride salt. LC-MS Method 1 t_(R)=1.26, min, m/z=401.

Example 22(E)-1-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

A solution of(E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-oneHCl salt (40 mg, 0.09 mmol) in CH₂Cl₂ (4 mL) was treated with i-Pr₂NEt(0.05 mL, 0.28 mmol) and MeSO₂Cl (0.014 mL, 0.18 mmol). The mixture wasstirred overnight at rt and applied to a 10-mL Chem-Elut cartridge thathad been wetted with 5% aq HCl (6 mL). The cartridge was eluted withether (20 mL). The eluate was concentrated and the residue was purifiedby prep HPLC to afford(E)-1-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one(20 mg, 45%). ¹H NMR (CDCl₃) 1.77 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H),2.13 (m, 1H), 2.92 (s, 3H), 3.00 (m, 1H), 3.23 (m, 1H), 3.47 (m, 1H),3.90 (m, 1H), 4.02 (m, 1H), 4.37 (m, 1H), 4.59 (m, 1H), 4.78 (d, 1H),6.82 (d, 1H), 7.05-7.75 (8H), 7.99 (d, 1H).

Example 23(E)-1-(2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 22 using acetic anhydride in place ofmethanesulfonyl chloride. ¹N NMR (CDCl₃) 1.64 (m, 2H), 1.81 (m, 1H),2.14 (m, 1H), 2.13 (3H), 3.08 (m, 1H), 3.60 (m, 2H), 4.0 (m, 1H), 4.39(d, 1H), 4.70 (3H), 6.82 (d, 1H), 7.1-7.75 (8H), 7.99 (d, 1H).

Example 24(E)-2-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1t_(R)=1.65, min, m/z=415; ¹H NMR (CDCl₃) 1.60 (d, 2H), 2.23 (m, 2H),3.06 (s, 3H), 3.46 (m, 1H), 3.84 (m, 1H), 4.23 (m, 1H), 4.86 (m, 1H),6.87 (d, 1H), 7.4-8.1 (9H)

Example 25(E)-7-chloro-2-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1t_(R)=1.75, min, m/z=449; ¹H NMR (CDCl₃) 1.85 (m, 2H), 2.99 (2H), 3.38(s, 3H), 3.68 (m, 1H), 3.90 (m, 1H), 4.0 (m, 1H), 4.48 (m, 1H), 6.82 (d,1H), 7.4-7.8 (7H), 8.0 (d, 1H).

Example 26(E)-7-chloro-1′-(3-(2,6-dichlorophenyl)acryloyl)-2-methylspiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one and2,6-dichlorocinnamic acid. ¹H NMR (CDCl₃) 1.82 (m, 2H), 2.99 (m, 2H),3.35 (s, 3H), 3.68 (m, 1H), 3.88 (m, 1H), 4.18 (m, 1H), 4.49 (m, 1H),7.06 (d, 1H), 7.1-7.6 (5H), 7.76 (2H).

Example 27(E)-7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using7-chlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1t_(R)=1.73, min, m/z=435.

Example 28(E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one

A mixture of 7-bromospiro[isoindoline-1,4′-piperidin]-3-one (194 mg,0.69 mmol), 3-(2-(trifluoromethyl)phenyl)acrylic acid (100 mg, 0.46mmol), EDCI (181 mg, 0.92 mmol), HOBt (124 mg, 0.92 mmol) and i-Pr₂NEt(1 mL) was stirred at rt overnight. The mixture was washed with 5% aqHCl, and the organic layer was concentrated to give a residue which waspurified by preparative HPLC to afford(E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one(5 mg, 2%). ¹H NMR (400 MHz, CDCl₃): δ=1.53 (m, 2H), 2.98 (m, 3H), 3.42(m, 1H), 4.23 (m, 1H), 4.50 (m, 1H), 4.93 (m, 1H), 6.80 (m, 1H), 7.33(m, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.65 (m, 3H), 7.77 (m, 1H), 7.95(m, 1H), 8.50 (m, 1H).

Example 29(E)-5,7-dichloro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 28 using5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. ¹H NMR (d₆-DMSO):1.47 (m, 2H), 2.58 (m, 1H), 3.06 (m, 1H), 4.44 (m, 1H), 4.61 (m, 1H),7.45 (m, 1H), 7.57 (m, 1H), 7.72 (m, 4H), 7.85 (m, 1H), 8.15 (m, 1H),9.96 (s, 1H).

Example 30(E)-1-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

To a stirred solution of6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (570 mg,2.45 mmol) in CH₂Cl₂ (20 mL) were added ortho-(trifluoromethyl)cinnamicacid (132 mg, 0.61 mmol), i-Pr₂NEt (0.43 mL, 2.45 mmol), HOBt (99 mg,0.73 mmol) and EDC.HCl (141 mg, 0.73 mmol). The mixture was stirred atrt for 3 d. The mixture was diluted with EtOAc (80 mL), washed withwater (30 mL) and satd aq NaHCO₃ (30 mL), and dried over Na₂SO₄. Removalof the solvent left an orange oil (378 mg). A portion of the oil waspurified by preparative HPLC to afford(E)-1-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one.LC-MS Method 1 t_(R)=1.37, min, m/z=431; ¹H NMR (CDCl₃) 2.25 (m, 4H),3.16 (br s, 2H), 3.39 (m, 1H), 3.45 (br s, 2H), 3.78 (s, 3H), 3.84 (m,1H), 4.11 (m, 1H), 4.78 (m, 1H), 4.9 (1H), 6.65 (s, 1H), 6.83 (m, 2H),7.12 (d, 1H), 7.4-7.75 (4H), 7.98 (d, 1H).

Example 31(E)-1-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one

A solution of 1-methylspiro[indoline-3,4′-piperidin]-2-one (100 mg, 0.46mmol) in CH₂Cl₂ (5 mL) was added 3-(2-trifluoromethyl-phenyl)-acrylicacid (120 mg, 0.56 mmol), HOBt (124 mg, 0.92 mmol), EDCI (181 mg, 0.92mmol) and DIEA (297 mg, 2.30 mmol). The reaction mixture was stirred atrt overnight. The above mixture was concentrated and the residue waspurified by preparative HPLC to give(E)-1-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one(50 mg, 26%). ¹H NMR (CDCl₃): 1.85-2.00 (m, 4H), 3.72 (s, 3H), 3.90-4.00(m, 2H), 4.15-4.30 (m, 1H), 4.40-4.50 (m, 1H), 6.80-6.90 (m, 2H),7.10-7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.45-7.60 (m, 2H), 7.68-7.72 (m,2H), 7.91-8.00 (m, 1H).

Example 32 (E)-methyl1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate

Step 1

To a solution of1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4′-piperidine]-5-carboxylicacid (2 g, 6.0 mmol) in methanol (30 mL) was added dropwise SOCl₂ (5 mL)at 0° C. Then the reaction mixture was stirred overnight at rt. Thereaction mixture was concentrated to give methyl2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (1.4 g,81%), which was used for the next step without purification. ¹H NMR(CD₃OD): 2.00 (m, 2H), 2.20 (m, 2H), 3.281 (m, 1H), 3.39 (m, 2H), 3.61(m, 2H), 3.85 (m, 2H), 3.88 (m, 2H), 7.00 (m, 1H), 7.98 (m, 2H).

Step 2

To a solution of methyl2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (400mg, 1.46 mmol) in anhydrous CH₂Cl₂ (10 mL) was added(E)-3-(2-(trifluoromethyl)phenyl)acrylic acid (315 mg, 1.46 mmol), HOBt(394 mg, 2.92 mmol), EDCI (576 mg, 2.92 mmol) and DIEA (942 mg, 7.30mol) at 0° C. and then stirred overnight at rt under N₂. Then thereaction mixture was washed with 1 N aq HCl and water. The organic layerwas dried over Na₂SO₄, filtered and concentrated to afford a residue,which was purified by preparative TLC to give (E)-methyl2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate(328 mg, 49%). ¹H NMR (CDCl₃): 1.58 (m, 4H), 1.97 (m, 3H), 3.91 (m, 3H),4.15 (m, 1H), 4.40 (m, 1H), 6.85 (m, 1H), 6.98 (m, 1H), 7.48 (m, 1H),7.56 (m, 1H), 7.72 (m, 1H), 7.99 (m, 2H).

Step 3

A solution of (E)-methyl2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate(150 mg, 0.33 mmol) in THF (3 mL) was added to a suspension of NaH (27mg, 0.66 mmol) in THF at 0° C. and stirred for 30 min at the sametemperature. Methyl iodide (58 mg, 0.41 mmol) was added to the abovemixture. The reaction mixture was stirred at rt for 2 h. The reactionmixture was poured into ice water and extracted with EtOAc (2×50 mL).The combined organic phases were dried over NaSO₄, filtered andconcentrated to give (E)-methyl1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate(90 mg, 58%). ¹H NMR (CD₃OD): 1.85-2.02 (m, 4H), 3.26 (s, 3H), 3.88 (s,3H), 3.95 (m, 1H), 4.15 (m, 1H), 4.28 (m, 1H), 7.10 (m, 1H), 7.26 (m,1H), 7.52 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H), 8.06 (m, 4H).

Example 33(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid

To a solution of (E)-methyl1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate(75 mg, 0.16 mmol) in methanol (4 mL) was added a solution of LiOH inH₂O (2 M, 4 mL) at rt and the mixture was stirred for 8 h at rt. Thereaction mixture was concentrated to remove methanol and extracted withCH₂Cl₂ twice. The combined organic phases were dried, filtered andconcentrated to give(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid (106 mg, 65%). ¹H NMR (CD₃OD): 1.94 (m, 4H), 3.26 (s, 3H), 4.15 (m,3H), 4.22 (m, 1H), 7.01 (d, 1H), 7.28 (d, 1H), 7.53 (m, 1H), 7.66 (m,1H), 7.76 (m, 1H), 8.01 (m, 3H), 8.08 (m, 1H).

Example 34(E)-N,N,1-trimethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide

To a mixture of(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid (20 mg, 0.508 mmol), EDCI (18 mg, 0.088 mmol), HOBt (12 mg, 0.088mmol), and DIEA (60 mg, 0.44 mmol) in CH₂Cl₂ was added NHMe₂.HCl (16 mg,0.176 mmol) at 0° C. The mixture was stirred at rt overnight. Themixture was concentrated to give the crude product, which was purifiedby preparative TLC to give(E)-N,N,1-trimethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide(6 mg, 14%). ¹H NMR (400 MHz, CDCl₃): δ=3.05 (m, 6H), 3.25 (m, 3H),3.60-3.75 (m, 2H), 3.95 (m, 2H), 4.15 (m, 1H), 4.35 (m, 1H), 6.85 (m,1H), 7.35 (m, 1H), 7.45 (m, 2H), 7.55 (m, 1H) 7.70 (m, 2H), 8.00 (m,1H).

Example 35(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide

To a solution of(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid (15 mg, 0.05 mmol) in anhydrous CH₂Cl₂ (4 mL) was added HOBt (15mg, 4 mL), EDCI (22 mg, 0.11 mmol) and DIEA (32 mg, 0.25 mmol) at 0° C.and the mixture was stirred overnight under NH₃ at rt. The reactionmixture was washed with 1 N aq HCl and the aqueous phase was extractedwith CH₂Cl₂ (2×). The combined organic phases were dried, filtered andconcentrated to give(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide(2.4 mg, 10%). ¹H NMR (CD₃OD): 1.94 (m, 4H), 3.27 (s, 3H), 4.01 (m, 1H),4.28 (m, 3H), 7.10 (d, 1H), 7.26 (d, 1H), 7.55 (m, 1H), 7.66 (m, 1H),7.76 (m, 1H), 8.00 (m, 4H).

Example 36(E)-N-(2-hydroxyethyl)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide

To a solution of(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid (20 mg, 0.04 mmol) in anhydrous CH₂Cl₂ (5 mL) was added2-aminoethanol (3.6 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) at 0° C. and the mixture wasstirred overnight at rt under N₂. The reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na₂SO₄, filteredand concentrated to afford a residue, which was purified by prep TLC togive(E)-N-(2-hydroxyethyl)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide(8 mg, 40%). ¹H NMR (CD₃OD): 1.90 (m, 4H), 3.25 (s, 3H), 3.50 (m, 2H),3.70 (m, 2H), 3.98 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H),7.26 (m, 1H), 7.53 (m, 1H), 7.68 (m, 1H), 7.75 (m, 1H), 7.90 (m, 2H),8.00 (m, 2H).

Example 37(E)-1-methyl-5-(4-methylpiperazine-1-carbonyl)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one

To a solution of(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylicacid (20 mg, 0.04 mmol) in anhydrous CH₂Cl₂ (5 mL) at 0° C. was added1-methyl-piperazine (6.0 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI(18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) and the mixture wasstirred overnight at rt under N₂. The reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na₂SO₄, filteredand concentrated to afford a residue, which was purified by prep TLC togive(E)-1-methyl-5-(4-methylpiperazine-1-carbonyl)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one(12 mg, 57%). ¹H NMR (CD₃OD): 1.90 (m, 4H), 2.95 (s, 3H), 3.30 (m, 11H),3.95 (m, 1H), 4.20 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H),7.50 (m, 3H), 7.66 (m, 1H), 7.77 (m, 1H), 8.00 (m, 2H).

Example 38(E)-N,1-dimethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 37 using methylamine hydrochloride. ¹H NMR: (400MHz, CDCl₃): δ=3.00 (m, 3H), 3.10 (m, 2H), 3.25 (m, 3H), 3.60-3.75 (m,2H), 4.00 (m, 2H), 4.15 (m, 1H), 4.35 (m, 1H), 6.70 (m, 1H), 6.90 (m,2H), 7.45 (m, 1H), 7.55 (m, 1H) 7.70 (m, 2H),), 7.85 (m, 2H), 8.00 (m,1H).

Example 39(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile

A solution of trifluoroacetic anhydride (34 mg, 0.157 mmol) in dioxane(4 mL) was added dropwise to a stirred, ice-cooled solution of(E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide(60 mg, 0.131 mmol) and pyridine (60 mg, 0.262 mmol). The reactionmixture was stirred at rt overnight. The mixture was diluted with waterand extracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to afford the crude product. After purification bypreparative HPLC, (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile wasobtained (2.04 mg, 4%). ¹H NMR: (400 MHz, CDCl₃): δ=1.85 (m, 4H), 3.20(m, 3H), 3.80-3.90 (m, 2H), 4.10 (m, 1H), 4.35 (m, 1H), 6.75 (m, 1H),6.85 (m, 1H), 7.40 (m, 2H), 7.50 (m, 1H), 7.55 (m, 1H) 7.65 (m, 2H),7.90 (m, 1H).

Example 40 (E)-methyl1-ethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 32 using ethyl iodide in Step 3. ¹H NMR (CDCl₃):1.25 (m, 3H), 1.86 (m, 4H), 1.82 (m, 2H), 3.77 (m, 2H), 3.91 (s, 3H),3.96 (m, 2H), 4.14 (m, 1H), 4.38 (m, 1H), 6.84 (m, 2H), 7.42 (m, 1H),7.54 (m, 1H), 7.69 (m, 2H), 7.92 (m, 1H), 7.98 (m, 2H).

Example 41(E)-5-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using5-fluorospiro[indoline-3,4′-piperidin]-2-one. LC-MS Method 1 t_(R)=1.77,min, m/z=419; ¹H NMR (CDCl₃) 1.95 (m, 4H), 3.94 (m, 2H), 4.15 (m, 1H),4.41 (m, 1H), 6.84 (m, 2H), 6.94 (m, 2H), 7.46 (m, 1H), 7.58 (m, 1H),7.64 (m, 2H), 7.99 (d, 1H).

Example 42(E)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one. LC-MS Method 1t_(R)=1.6, min, m/z=415; ¹H NMR (CDCl₃) 1.93 (m, 2H), 2.05-2.30 (3H),3.16 (m, 1H), 3.62 (m, 1H), 3.70 (s, 2H), 4.14 (m, 1H), 4.84 (m, 1H),6.83 (d, 1H), 7.19 (m, 1H), 7.29 (s, 2H), 7.48 (m, 1H), 7.58 (m, 2H),7.69 (m, 2H), 8.00 (d, 1H).

Example 43(E)-1,1-dimethyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-1H-spiro[isoquinoline-4,4′-piperidin]-3(2H)-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using1,1-dimethyl-1H-spiro[isoquinoline-4,4′-piperidin]-3(2H)-one. LC-MSMethod t_(R)=1.78, min, m/z=443; ¹H NMR (CDCl₃) 1.61 (s, 6H), 2.13 (4H),3.64 (m, 1H), 4.02 (m, 1H), 4.20 (m, 1H), 4.61 (m, 1H), 6.77 (s, 1H),6.85 (d, 1H), 7.20-7.50 (5H), 7.58 (m, 1H), 7.69 (m, 2H), 7.99 (d, 1H).

Example 441-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-2-(2-(trifluoromethyl)phenyl)ethanone

The title compound was prepared following a procedure analogous to thatdescribed in Example 30 using 2-(2-(trifluoromethyl)phenyl)acetic acid.LC-MS Method 1 t_(R)=1.27, min, m/z=419

Example 457-chloro-1′-(2-(2-(trifluoromethyl)phenyl)acetyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 28 using 2-(2-(trifluoromethyl)phenyl)acetic acid.LC-MS Method 1 t_(R)=1.63, min, m/z=425, 423

Example 46(±)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-2-(2-(trifluoromethyl)phenyl)ethanone

The title compound was prepared following a procedure analogous to thatdescribed in Example 18 using 2-(2-(trifluoromethyl)phenyl)acetic acidin Step 4. LC-MS Method 1 t_(R)=1.35, min, m/z=469, 467

Example 471′-(2-(2-(trifluoromethyl)phenyl)acetyl)spiro[indoline-3,4′-piperidin]-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acidand spiro[indoline-3,4′-piperidin]-2-one. LC-MS Method 3 t_(R)=1.089,min, m/z=389; NMR (CDCl₃) 1.19 (m, 1H), 1.28 (m, 1H), 1.75 (m, 4H), 3.62(m, 1H), 3.88 (m, 5H), 6.81 (d, 2H), 6.93 (m, 1H), 7.13 (m, 2H), 7.35(m, 2H), 7.47 (m, 1H), 7.61 (d, 1H), 8.41 (s, 1H)

Example 481-methyl-1′-(2-(2-(trifluoromethyl)phenyl)acetyl)spiro[indoline-3,4′-piperidin]-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acid.LC-MS Method 3 t_(R)=1.199, min, m/z=403; ¹H NMR (CDCl₃) 1.68-1.82 (m,4H), 3.14 (s, 3H), 3.65 (d, 1H), 3.75 (m, 1H), 4.0 (m, 3H), 4.28 (d,1H), 6.70 (d, 1H), 7.02 (t, 1H), 7.12 (d, 1H), 7.25 (t, 1H), 7.33 (d,2H), 7.50 (t, 1H), 7.62 (d, 1H).

Example 497-bromo-1′-(2-(2-(trifluoromethyl)phenyl)acetyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acidand 7-bromospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 2t_(R)=2.092, min, m/z=469; ¹H NMR (CDCl₃) 1.35 (d, 1H), 1.43 (d, 1H),2.72 (m, 1H), 2.90 (m, 2H), 3.40 (t, 1H), 3.80-4.05 (m, 3H), 4.88 (d,1H), 7.31 (t, 2H), 7.38 (d, 1H), 7.48 (t, 1H), 7.61 (d, 1H), 7.68 (d,1H), 7.78 (d, 1H), 9.17 (s, 1H).

Example 505,7-dichloro-1′-(2-(2-(trifluoromethyl)phenyl)acetyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acidand 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 3t_(R)=1.246, min, m/z=457; ¹H NMR (CDCl₃) 1.43 (d, 2H), 2.62 (m, 1H),2.78 (m, 1H), 2.90 (t, 1H), 3.40 (t, 1H), 3.88-4.11 (m, 3H), 4.93 (d,1H), 7.43 (m, 2H), 7.54 (m, 2H), 7.70 (d, 1H), 7.77 (s, 1H), 8.74 (s,1H)

Example 512-(7-chloro-1′(2-(2-(trifluoromethyl)phenyl)acetyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 2-(2-(trifluoromethyl)phenyl)acetic acidand ethyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MSMethod 1 t_(R)=1.83, min, m/z=468, 466

Example 522-(7-chloro-1′-(2-(2-(trifluoromethoxy)phenyl)acetyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 2-(2-(trifluoromethoxy)phenyl)acetic acid andethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate.LC-MS Method 1 t_(R)=1.88, min, m/z=484, 482

Example 532-(7-chloro-1′(2-(4-fluoro-2-(trifluoromethyl)phenyl)acetyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid and ethyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MSMethod 1 t_(R)=1.88, min, m/z=486, 484

Example 542-(7-chloro-1′(2-(4-chloro-2-(trifluoromethyl)phenyl)acetyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid and ethyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MSMethod 1 t_(R)=2.00, min, m/z=500.

Example 552-methyl-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand 2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1t_(R)=1.65, min, m/z=417, 415.

Example 56 Ethyl2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MSMethod 1 t_(R)=2.27, min, m/z=554, 552

Example 57 tert-butyl1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand tert-butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate.LC-MS Method 1 t_(R)=2.18, min, m/z=503

Example 582-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 2. LC-MSMethod 1 t_(R)=1.95, min, m/z=526, 524

Example 591-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-one

The title compound was prepared from tert-butyl1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylatefollowing a procedure analogous to that described in Example 21. LC-MSMethod 1 t_(R)=1.32, min, m/z=403

Example 601-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-one

The title compound was prepared from1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-onefollowing a procedure analogous to that described in Example 22. LC-MSMethod 1 t_(R)=1.78, min, m/z=481

Example 617-chloro-2-methyl-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand 7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MSMethod 1 t_(R)=1.77, min, m/z=453, 451

Example 621-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 30 using 3-(2-(trifluoromethyl)phenyl)propanoicacid. LC-MS Method 1 t_(R)=1.32, min, m/z=433

Example 631-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-o-tolylpropane-1-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 30 using 3-o-tolylpropanoic acid. LC-MS Method 1t_(R)=1.23, min, m/z=379

Example 641-(7-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-one

The title compound was prepared from7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indene-1,4′-piperidin]-3(2H)-onefollowing a procedure analogous to that described in Example 16. LC-MSMethod 1 t_(R)=1.87, min, m/z=484, 482

Example 657-chloro-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand 7-chlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1t_(R)=1.73, min, m/z=437

Example 661-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 18 using 3-(2-(trifluoromethyl)phenyl)propanoicacid in Step 4. LC-MS Method 1 t_(R)=1.4, min, m/z=483, 481

Example 671′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidin]-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 3-(2-(trifluoromethyl)phenyl)propanoicacid and spiro[indoline-3,4′-piperidin]-2-one. LC-MS Method 3t_(R)=1.157, min, m/z=403; ¹H NMR (CDCl₃) 1.39 (m, 2H), 1.47 (m, 2H),1.65 (m, 2H), 1.78 (m, 3H), 2.62 (m, 2H), 3.15 (m, 2H), 3.61 (m, 2H),3.83 (m, 2H), 4.17 (m, 1H), 6.83 (d, 1H), 6.97 (m, 1H), 7.15 (m, 2H),7.26 (m, 1H), 7.38 (m, 1H), 7.43 (m, 1H), 7.58 (d, 1H), 7.84 (s, 1H).

Example 68N-methyl-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxamide

The title compound was prepared from1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)propan-1-onefollowing a procedure analogous to that described in Example 19. LC-MSMethod 1 t_(R)=1.72, min, m/z=460

Example 691-methyl-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidin]-2-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 31 using 3-(2-(trifluoromethyl)phenyl)propanoicacid. LC-MS Method 3 t_(R)=1.262, min, m/z=417; ¹H NMR (CDCl₃) 1.62 (m,1H), 1.75 (m, 2H), 2.62 (m, 2H), 3.15 (s, 5H), 3.58 (m, 1H), 3.72-3.92(m, 2H), 4.18 (m, 1H), 6.80 (d, 1H), 7.0 (t, 1H), 7.17 (d, 1H), 7.25 (m,2H), 7.38-7.48 (m, 2H), 7.58 (d, 1H).

Example 70(S)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

Isomers 1 and 2 of the title compound were prepared following aprocedure analogous to that described for Example 2 Isomers 1 and 2using 3-(2-(trifluoromethyl)phenyl)propanoic acid in Step 2.

Isomer 1: LC-MS Method 3 t_(R)=1.334, min, m/z=526; ¹H NMR (CDCl₃) 1.48(d, 2H), 1.62 (m, 1H), 2.31 (m, 1H), 2.43 (m, 1H), 2.50-2.80 (m, 4H),2.88-3.20 (m, 5H), 3.52 (m, 1H), 3.75 (d, 1H), 4.68 (d, 1H), 7.0 (t,1H), 7.08 (d, 1H), 7.25 (t, 1H), 7.31 (d, 1H), 7.40 (m, 2H), 7.56 (d,1H).

Isomer 2: LC-MS Method 3 t_(R)=1.346, min, m/z=526; ¹H NMR (CDCl₃) 1.48(d, 2H), 1.70 (m, 1H), 2.30-2.60 (m, 2H), 2.62-2.88 (m, 4H), 2.95-3.30(m, 5H), 3.60 (m, 1H), 3.82 (d, 1H), 4.73 (d, 1H), 7.10 (t, 1H), 7.13(d, 1H), 7.32 (t, 1H), 7.45 (m, 3H), 7.65 (d, 1H).

Example 717-bromo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoicacid and 7-bromospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 2t_(R)=2.206, min, m/z=481; ¹H NMR (CDCl₃) 1.43 (d, 2H), 2.68 (t, 2H),2.80-2.92 (m, 3H), 3.15 (t, 2H), 3.32 (t, 1H), 3.92 (d, 1H), 4.85 (d,1H), 7.25 (m, 2H), 7.40 (m, 2H), 7.56 (d, 1H), 7.65 (d, 1H), 7.79 (d,1H), 9.20 (s, 1H).

Example 725,7-dichloro-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[isoindoline-1,4′-piperidin]-3-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoicacid and 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MSMethod 3 t_(R)=1.312, min, m/z=471; ¹H NMR (d₆-DMSO) 1.38 (d, 2H), 2.37(m, 1H), 2.60-2.80 (m, 2H), 2.83-3.02 (m, 3H), 3.35 (m, 2H), 3.94 (d,1H), 4.51 (d, 1H), 7.38 (t, 1H), 7.55 (m, 2H), 7.64 (m, 2H), 7.80 (s,1H), 9.88 (s, 1H)

Example 732-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acidand ethyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that in Example 2. LC-MS Method 1t_(R)=1.93, min, m/z=482, 480

Example 742-(7-chloro-1′-(3-(2-chlorophenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2-chlorophenyl)propanoic acid and ethyl2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that in Example 2. LC-MS Method 1t_(R)=1.87, min, m/z=446

Example 752-(7-chloro-1′-(3-(2,4-dichlorophenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 3-(2,4-dichlorophenyl)propanoic acid andethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowed by a procedure analogous to that in Example 2. LC-MS Method 1t_(R)=2.03, min, m/z=484, 482, 480

Example 761-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 32 using 3-(2-(trifluoromethyl)phenyl)propanoicacid in Step 2. LC-MS Method 3 t_(R)=1.257, min, m/z=475; ¹H NMR (CDCl₃)1.63 (m, 2H), 1.70-1.82 (m, 3H), 2.70 (m, 2H), 3.24 (m, 5H), 3.65 (m,1H), 3.81 (m, 1H), 3.93 (m, 4H), 4.28 (m, 1H), 6.89 (d, 1H), 7.37 (t,1H), 7.46 (d, 1H), 7.53 (t, 1H), 7.65 (d, 1H), 7.88 (s, 1H), 8.05 (d,1H).

Example 771-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carboxamide

The title compound was prepared from1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carboxylatefollowing a procedure analogous to those described in Examples 33 and35. LC-MS Method 2 t_(R)=2.022, min, m/z=482; ¹H NMR (CD₃OD) 1.78 (m,2H), 1.84 (m, 2H), 2.83 (m, 2H), 3.20 (t, 2H), 3.28 (s, 3H), 3.83 (m,1H), 3.98 (m, 2H), 4.20 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.55 (d,1H), 7.64 (t, 1H), 7.71 (d, 1H), 7.95 (m, 2H).

Example 78 Methyl1-ethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 32 using 3-(2-(trifluoromethyl)phenyl)propanoicacid in Step 2 and ethyl iodide in Step 3. LC-MS Method 3 t_(R)=1.327,min, m/z=511.1; ¹H NMR (CD₃OD) 1.24 (m, 3H), 1.60-1.75 (m, 2H), 1.80 (m,2H), 2.75 (m, 1H), 2.85 (m, 1H), 3.19 (t, 2H), 3.78 (m, 4H), 3.91 (s,1H), 4.21 (m, 1H), 4.58 (s, 1H), 7.12 (d, 1H), 7.44 (t, 1H), 7.54 (d,1H), 7.63 (t, 1H), 7.69 (d, 1H), 7.94 (s, 1H), 8.04 (d, 1H)

Example 791-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile

The title compound was prepared from1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)spiro[indoline-3,4′-piperidine]-5-carboxamidefollowing a procedure analogous to that described in Example 39. LC-MSMethod 3 t_(R)=1.219, min, m/z=442.1; ¹H NMR (CDCl₃) 1.62 (m, 1H), 1.80(m, 3H), 2.76 (m, 2H), 3.18 (m, 2H), 3.22 (s, 3H), 3.65 (m, 1H), 3.78(m, 1H), 3.94 (m, 1H), 4.32 (m, 1H), 6.90 (d, 1H), 7.40 (m, 3H), 7.53(t, 1H), 7.63 (t, 2H)

Example 802-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetamide

The title compound was prepared from2-(7-chloro-1′-(3-(2-(trifluoromethyl)phenyl)propanoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 13.LC-MS Method 1 t_(R)=1.78, min, m/z=481, 479.

Example 81 Ethyl2-(7-bromo-1′4(2-chloro-6-fluorobenzyl)(ethyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

LC-MS Method 1 t_(R)=2.33, min, m/z=565.

Example 82 Ethyl2-(7-bromo-1′-(2-ethoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 19 using 2-ethoxybenzyl isocyanate and ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. ¹H NMR(CDCl₃) [selected resonances] 1.28 (t, 3H), 1.44 (t, 3H), 4.11 (q, 2H),4.19 (q, 2H), 4.45 (s, 2H).

Example 832-(7-bromo-1′-(2,4,5-trifluorobenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2,4,5-trifluorobenzyl isocyanate followedby a procedure analogous to that described in Example 2. LC-MS Method 1t_(R)=1.72, min, m/z=513, 511

Example 842-(7-bromo-1′-(2-ethoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(2-ethoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.77, min, m/z=503, 511

Example 85N-(biphenyl-2-ylmethyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 19. LC-MS Method 1 t_(R)=1.95, min, m/z=399.

Example 86 Ethyl2-(7-bromo-1′(2-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-methylbenzyl isocyanate. LC-MS Method 1t_(R)=2.01, min, m/z=499, 501(M+1).

Example 872-(7-bromo-1′-(2-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(2-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.68, min, m/z=471, 473(M+1)

Example 88 tert-butyl4-(2-(7-bromo-1′-(2-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetyl)piperazine-1-carboxylate

LC-MS Method 1 t_(R)=1.95, min, m/z=639, 641(M+1)

Example 89 Ethyl2-(7-bromo-1′-(2-chloro-6-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-chloro-6-methylbenzyl isocyanate. LC-MSMethod 1 t_(R)=2.11, min, m/z=533, 535(M+1)

Example 907-bromo-N-(2-methylbenzyl)-3-(2-oxo-2-(piperazin-1-yl)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from tert-butyl4-(2-(7-bromo-1′-(2-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetyl)piperazine-1-carboxylateusing a procedure analogous to that described in Example 21. LC-MSMethod 1 t_(R)=1.32, min, m/z=539, 541(M+1)

Example 912-(7-bromo-1′-(2-chloro-6-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(2-chloro-6-methylbenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.78, min, m/z=505, 507(M+1).

Example 92 Ethyl2-(7-bromo-1′-(2-(trifluoromethyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-(trifluoromethyl)benzyl isocyanate.LC-MS Method 1 t_(R)=2.08, min, m/z=553, 555(M+1)

Example 93 Ethyl2-(7-bromo-1′-(2-(methylsulfonyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-(methylsulfonyl)benzyl isocyanate. LC-MSMethod 1 t_(R)=1.8, min, m/z=563, 565(M+1)

Example 942-(7-bromo-1′-(2-(trifluoromethyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(2-(trifluoromethyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.78, min, m/z=525, 527(M+1)

Example 95 Ethyl2-(7-bromo-1′-(2-isopropoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-(isopropoxy)benzyl isocyanate. LC-MSMethod 1 tR=2.13, min, m/z=543, 545(M+1)

Example 962-(7-bromo-1′-(2-(pyrrolidin-1-yl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 82 using 2-(pyrrolidin-1-yl)benzyl isocyanatefollowed by a procedure analogous to that described in Example 2. LC-MSMethod 1 tR=1.35, min, m/z=526, 528(M+1)

Example 972-(7-bromo-1′-(2-(methylsulfonyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(2-(methylsulfonyl)benzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 tR=1.49, min, m/z=535, 537(M+1)

Example 982-(7-bromo-1′-(2-isopropoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-F-(2-isopropoxybenzylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 tR=1.8, min, m/z=515, 517(M+1)

Example 997-bromo-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 19. LC-MS Method 1 t_(R)=1.85, min, m/z=499, 497.

Example 1007-chloro-2-methyl-3-oxo-N-(2-(trifluoromethyl)benzyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 19. LC-MS Method 1 t_(R)=1.59, min, m/z=452,454(M+1).

Example 101 Ethyl2-(7-bromo-1′-(methyl(2-(trifluoromethyl)benzyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

LC-MS Method 1 t_(R)=2.33, min, m/z=567, 569(M+1).

Example 1022-(7-bromo-1′-(methyl(2-(trifluoromethyl)benzyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′-(methyl(2-(trifluoromethyl)benzyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.99, min, m/z=539, 541(M+1).

Example 103 Ethyl2-(7-bromo-1′-((2-fluorobenzyl)(methyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared by analogy with Example 101. LC-MSMethod 1 t_(R)=2.21, min, m/z=517, 519(M+1).

Example 1042-(7-bromo-1′((2-fluorobenzyl)(methyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from ethyl2-(7-bromo-1′4(2-fluorobenzyl)(methyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateusing a procedure analogous to that described in Example 2. LC-MS Method1 t_(R)=1.86, min, m/z=489, 491(M+1).

Example 105 2-(trifluoromethyl)benzyl7-bromo-3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

To o-(trifluoromethyl)benzyl alcohol (35 mg, 0.20 mmol) in CH₂Cl₂ (4 mL)was added was a solution of carbonyl diimidazole (29 mg, 0.18 mmol) inCH₂Cl₂ (4 mL). The mixture was stirred at rt for 2 h. A 1-mL aliquot ofthe resulting solution (0.05 mmol) was added to a solution7-bromospiro[indene-1,4′-piperidin]-3(2H)-one (14.5 mg, 0.05 mmol) inCH₂Cl₂ (1 mL). The mixture was stirred at rt for 16 h, concentrated,redissolved in MeCN (1 mL) and heated at 60° C. for 2 h. Prep HPLCafforded the title compound. LC-MS Method 1 t_(R)=2.06, min, m/z=484,482.

Example 1067-bromo-1′-(2-(2-(trifluoromethyl)phenoxy)acetyl)spiro[indene-1,4′-piperidin]-3(2H)-one

The title compound was prepared following a procedure analogous to thatdescribed in Example 1. LC-MS Method 1 t_(R)=1.90 min, m/z=484, 482.

Example 1077-bromo-1′-(2-(2-(trifluoromethyl)phenylamino)acetyl)spiro[indene-1,4′-piperidin]

The title compound was prepared following a procedure analogous to thatdescribed in Example 1. LC-MS Method 1 t_(R)=2.00 min, m/z=483, 481.

Biological Test Example 1

The inhibition of microsomal preparation of 11β-HSD1 by compounds of theinvention was measured essentially as previously described (K. Solly, S.S. Mundt, H. J. Zokian, G. J. Ding, A. Hermanowski-Vosatka, B.Strulovici, and W. Zheng, High-Throughput Screening of11-Beta-Hydroxysteroid Dehydrogenase Type 1 in Scintillation ProximityAssay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactionswere carried out at rt in 96 well clear flexible PET Microbeta plates(PerkinElmer). The assay begins by dispensing 49 μl of substratesolution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 2 mMNADPH and 160 nM [³H]cortisone (1 Ci/mmol)) and mixing in 1 μL of thetest compounds in DMSO previously diluted in half-log increments (8points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL ofenzyme solution containing microsomes isolated from CHO cellsoverexpressing human 11β-HSD1 (10-20 μg/ml of total protein) was added,and the plates were incubated for 90 minutes at rt. The reaction wasstopped by adding 50 μl of the SPA beads suspension containing 10 μM18β-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GEHealthcare) and 3.3 μg/ml of anti-cortisol antibody (East CoastBiologics) in Superblock buffer (Bio-Rad). The plates were shaken for120 minutes at rt, and the SPA signal corresponding to [³H]cortisol wasmeasured on a Microbeta plate reader.

Biological Test Example 2

The inhibition of 11β-HSD1 by compounds of this invention was measuredin whole cells as follows. Cells for the assay were obtained from twosources: fully differentiated human omental adipocytes from Zen-Bio,Inc.; and human omental pre-adipocytes from Lonza Group Ltd.Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchasedin 96-well plates and were used in the assay at least two weeks afterdifferentiation from precursor preadipocytes. Zen-Bio induceddifferentiation of pre-adipocytes by supplementing medium withadipogenic and lipogenic hormones (human insulin, dexamethasone,isobutylmethylxanthine and PPAR-gamma agonist). The cells weremaintained in full adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPESpH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B,supplied by Zen-Bio, Inc.) at 37° C., 5% CO₂.

Pre-adipocytes were purchased from Lonza Group Ltd. and placed inculture in Preadipocyte Growth Medium-2 supplemented with fetal bovineserum, penicillin, and streptomycin (supplied by Lonza) at 37° C., 5%CO₂. Pre-adipocytes were differentiated by the addition of insulin,dexamethasone, indomethacin and isobutyl-methylxanthine (supplied byLonza) to the Preadipocyte Growth Medium-2. Cells were exposed to thedifferentiating factors for 7 days, at which point the cells weredifferentiated and ready for the assay. One day before running theassay, the differentiated omental adipocytes were transferred intoserum- and phenol-red-free medium for overnight incubation. The assaywas performed in a total volume of 200 μL. The cells were pre-incubatedwith serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSOand various concentrations of the test compounds at least 1 h before[³H] cortisone in ethanol (50 Ci/mmol, ARC, Inc.) was added to achieve afinal concentration of cortisone of 100 nM. The cells were incubated for3-4 hrs at 37° C., 5% CO₂. Negative controls were incubated withoutradioactive substrate and received the same amount of [³H] cortisone atthe end of the incubation. Formation of [³H] cortisol was monitored byanalyzing 25 μL of each supernatant in a scintillation proximity assay(SPA). (Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.;Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev.Technol. 2005, 3, 377-384). Many compounds of the invention showedsignificant activity in this assay.

TABLE OF BIOLOGICAL ASSAY RESULTS Biological Test Example 1 Average %inhibition at Average % Compound IC₅₀ Range^(a) 100 nM inhibition at 111nM EXAMPLE 1 ++ 94.9 89.4 EXAMPLE 2 ++ 91.7 97.4 EXAMPLE 2.1 ++ 96.6EXAMPLE 2.2 ++ 100.3 EXAMPLE 3 ++ 96.3 EXAMPLE 4 ++ 94.2 EXAMPLE 5 ++83.3 EXAMPLE 6 ++ 97.4 EXAMPLE 7 ++ 87.3 EXAMPLE 8 ++ 85.5 EXAMPLE 9 ++77.8 EXAMPLE 10 ++ 87.7 EXAMPLE 11 ++ 75.1 EXAMPLE 12 ++ 90.3 EXAMPLE 13++ 94.6 94.8 EXAMPLE 14 ++ 85.6 90.9 EXAMPLE 15 ++ 95.3 92.6 EXAMPLE 16++ 95.3 98.6 EXAMPLE 17 ++ 81.2 EXAMPLE 18 ++ 93.3 EXAMPLE 19 ++ 98.1EXAMPLE 20 ++ 29.0 EXAMPLE 21 ++ 87.4 EXAMPLE 22 ++ 95.3 EXAMPLE 23 ++94.9 EXAMPLE 24 ++ 82.3 EXAMPLE 25 ++ 95.5 95.3 EXAMPLE 26 ++ 79.0EXAMPLE 27 ++ 89.8 EXAMPLE 28 ++ 92.7 EXAMPLE 29 ++ 94.2 EXAMPLE 30 ++90.3 94.6 EXAMPLE 31 ++ 99.9 EXAMPLE 32 ++ 83.4 EXAMPLE 33 + 31.5EXAMPLE 34 + 38.2 EXAMPLE 35 + 41.4 EXAMPLE 36 + 0.6 EXAMPLE 37 + 7.1EXAMPLE 38 + 21.3 EXAMPLE 39 ++ 64.8 EXAMPLE 40 ++ 71.2 EXAMPLE 41 ++91.2 EXAMPLE 42 ++ 79.3 EXAMPLE 43 ++ 90.6 EXAMPLE 44 ++ 69.9 EXAMPLE45 + 43.2 EXAMPLE 46 ++ 78.6 EXAMPLE 47 ++ 83.3 EXAMPLE 48 ++ 80.6 86.3EXAMPLE 49 + 49.2 EXAMPLE 50 + 68.9 EXAMPLE 51 ++ 76.8 EXAMPLE 52 ++61.2 EXAMPLE 53 ++ 67.2 EXAMPLE 54 ++ 71.7 EXAMPLE 55 ++ 76.5 EXAMPLE 56++ 92.7 EXAMPLE 57 + 37.6 EXAMPLE 58 ++ 97.1 87.4 EXAMPLE 59 ++ 66.6EXAMPLE 60 ++ 92.6 EXAMPLE 61 ++ 93.3 96.7 EXAMPLE 62 ++ 87.2 EXAMPLE63 + 22.5 EXAMPLE 64 ++ 100.0 EXAMPLE 65 ++ 87.7 EXAMPLE 66 ++ 92.1EXAMPLE 67 ++ 100.3 EXAMPLE 68 ++ 81.5 EXAMPLE 69 ++ 93.5 93.8 EXAMPLE70.1 ++ 97.6 EXAMPLE 70.2 ++ 95.7 99.2 EXAMPLE 71 ++ 93.9 EXAMPLE 72 ++82.4 EXAMPLE 73 ++ 96.6 95.4 EXAMPLE 74 ++ 89.5 EXAMPLE 75 ++ 52.2EXAMPLE 76 ++ 60.0 EXAMPLE 77 + 26.3 EXAMPLE 78 ++ 52.4 EXAMPLE 79 +51.4 EXAMPLE 80 ++ 95.1 EXAMPLE 81 ++ 59.2 EXAMPLE 82 + 28.6 EXAMPLE83 + 10.9 EXAMPLE 84 + 42.6 EXAMPLE 85 + 19.4 EXAMPLE 86 ++ 58.7 EXAMPLE87 ++ 57.2 EXAMPLE 88 ++ 66.2 EXAMPLE 89 ++ 61.2 EXAMPLE 90 + 52.4EXAMPLE 91 ++ 64.1 EXAMPLE 92 ++ 70.5 EXAMPLE 93 + 18.5 EXAMPLE 94 ++75.7 EXAMPLE 95 + 19.9 EXAMPLE 96 + 48.9 EXAMPLE 97 + 5.6 EXAMPLE 98 ++48.2 EXAMPLE 99 ++ 75.6 EXAMPLE 100 + 46.8 EXAMPLE 101 + 42.6 EXAMPLE102 ++ 64.4 EXAMPLE 103 ++ 79.4 EXAMPLE 104 ++ 88.7 EXAMPLE 105 ++ 82.3EXAMPLE 106 ++ EXAMPLE 107 + ^(a)++ means IC₅₀ = <100 nM, + means IC₅₀ =100-1000 nM, # means IC₅₀ > 100 nM, − means IC₅₀ > 1000 nM.

Prophetic Examples

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually designated as having been incorporated by reference. Itis understood that the examples and embodiments described herein are forillustrative purposes only, and it will be appreciated that theinvention is susceptible to modification, variation and change withoutdeparting from the proper scope or fair meaning of the appended claims.

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: A is amonocyclic heteroaromatic group or a phenyl group; R¹ is independentlyhalo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹²,OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹²,SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹²,NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, NR¹¹SO₂R¹³ or HetCy; or a (C₁-C₆)alkylsubstituted with halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹,CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹²,OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹²,SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹²,NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; each R² is independentlyhydrogen, halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹,CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a(C₁-C₆)alkyl substituted with halo, OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹,C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, NR¹¹R¹²,CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹²,NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹²,NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; m is an integerfrom 0-3; p is 0, 1 or 2; s is 1 or 2; t is 1 or 2; K, L and M areindependently selected from O, NR⁴, CR^(4a)R^(4b) or CO; provided: i)that no more than one of K, L and M is CO; ii) that K-L and L-M are not—O—O—; and iii) that K-L-M- is not —O—NR⁴—O— or —NR⁴—NR⁴—NR⁴—; each R⁴is independently hydrogen, (C₁-C₆)alkyl, C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴,C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar or HetAr; or(C₁-C₆)alkyl substituted with OH, NR¹⁴R¹⁵, C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴,C(S)OR¹⁴, C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹⁴C(O)NR¹⁴R¹⁵, NR¹⁴C(S)NR¹⁴R¹⁵,OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, NR¹⁴C(O)OR¹⁴, NR¹⁴C(S)OR¹⁴, SO₂R¹⁴,NR¹⁴SO₂R¹⁴, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂NR¹⁴R¹⁵, Ar or HetAr; each R^(4a) andeach R^(4b) is independently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵,C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴, C(O)NHSO₂R¹⁴, C(S)NHSO₂R¹⁴,C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(S)R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵,NR¹¹C(S)NR¹⁴R¹⁵, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(S)NHSO₂R¹⁴, OC(O)R¹⁴, OC(S)R¹⁴,OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴, OC(S)NHSO₂R¹⁴, NR¹¹C(O)OR¹⁴,NR¹¹C(S)OR¹⁴, SO₂R¹⁴, NR¹¹SO₂R¹⁴, SO₂NR¹⁴R¹⁵, NR¹¹SO₂NR¹⁴R¹⁵, Ar, HetAr,or HetCy; or (C₁-C₆)alkyl optionally substituted with OH, NR¹⁴R¹⁵,C(O)R¹⁴, C(S)R¹⁴, C(O)NHSO₂R¹⁴, C(S)NHSO₂R¹⁴, COOR¹⁴, C(S)OR¹⁴,C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, NR¹¹C(O)NR¹⁴R¹⁵, NR¹¹C(S)NR¹⁴R¹⁵,OC(O)NR¹⁴R¹⁵, OC(S)NR¹⁴R¹⁵, NR¹¹C(O)OR¹⁴, NR¹¹C(S)OR¹⁴, SO₂R¹⁴,NR¹¹SO₂R¹⁴, SO₂NR¹⁴R¹⁵, Ar, HetAr, or HetCy; W, X, Y and Z areindependently selected from N, CR⁵, provided that no more than two of W,X, Y and Z are N; each R⁵ is independently selected from hydrogen, halo,OR¹¹, S(O)_(p)R¹¹, CN, NO₂, COR¹¹, CSR¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹²,NR¹¹C(O)NR¹¹R¹², CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹²,NR¹¹SO₂NR¹¹R¹², NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³,NR¹¹C(S)OR¹³, or NR¹¹SO₂R¹³; or a (C₁-C₆)alkyl substituted with halo,OR¹¹, S(O)_(p)R¹¹, CN, NO₂, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, CHO, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, NR¹¹R¹², CONR¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹²,CSNR¹¹R¹², OC(S)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹²,NR¹¹C(O)R¹², OC(O)R¹², NR¹¹C(S)R¹², NR¹¹C(O)OR¹³, NR¹¹C(S)OR¹³, orNR¹¹SO₂R¹³; each R¹¹ and each R¹² is independently selected fromhydrogen, (C₁-C₆)alkyl or (C₁-C₆)hydroxyalkyl; R¹³ is (C₁-C₆)alkyl or(C₁-C₆)hydroxyalkyl; each R¹⁴ and each R¹⁵ is independently hydrogen or(C₁-C₆)alkyl, optionally substituted with OR¹¹, NR¹¹R¹², C(O)R¹¹,C(S)R¹¹, COOR¹¹, C(S)OR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², NR¹¹C(O)R¹¹,NR¹¹C(S)R¹¹, NR¹¹C(O)NR¹¹R¹², NR¹¹C(S)NR¹¹R¹², NR¹¹C(O)NHSO₂R¹¹,NR¹¹C(S)NHSO₂R¹¹, OC(O)R¹¹, OC(S)R¹¹, OC(O)NR¹¹R¹², OC(S)NR¹¹R¹²,OC(O)NHSO₂R¹¹, OC(S)NHSO₂R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(S)OR¹¹, SO₂R¹¹,NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², NR¹¹SO₂NR¹¹R¹², Ar, HetAr, or HetCy; or NR¹⁴R¹⁵taken together forms a 4, 5, 6- or 7-membered heterocyclic groupcontaining 1 or 2 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfuratoms, said ring being optionally substituted at any one or moresubstitutable ring carbon with oxo, hydroxy, or (C₁-C₃)alkyl, andoptionally substituted at any one or more substitutable ring nitrogenwith (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ or C(O)NR¹¹R¹²; each Ar is aryloptionally substituted with halogen, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN, CONH₂,(C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy; each HetAr is heteroaryloptionally substituted with halogen, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, NO₂, CN, CONH₂,(C₁-C₆)haloakyl or (C₁-C₆)haloalkoxy; and each HetCy is a monocyclicheterocyclic group containing at least one ring atom selected fromnitrogen, oxygen or sulfur, said ring being optionally substituted atany one or more substitutable ring carbon with oxo, hydroxy, or(C₁-C₃)alkyl, and optionally substituted at any one or moresubstitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².
 2. A compound represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 4. A compound representedby the following structural formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim6, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 8. A compound representedby the following structural formula:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim8, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim10, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 12. A compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim12, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim14, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim16, wherein the compound is represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim3, wherein R¹ is halo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, or(C₁-C₃)haloalkoxy.
 19. The compound of claim 18, wherein m=0.
 20. Thecompound of claim 18, wherein m=1; and each R² is independentlyhydrogen, halo, (C₁-C₃)alkyl, hydroxy, hydroxy(C₁-C₃)alkyl,COO(C₁-C₃)alkyl, CONH₂, (C₁-C₃)alkoxy, (C₁-C₃)alkylamino,di(C₁-C₃)alkylamino, NO₂, CN, (C₁-C₃)haloalkyl or (C₁-C₃)haloalkoxy. 21.The compound of claim 20, wherein each R⁴ is independently hydrogen,(C₁-C₆)alkyl, C(O)R¹⁴, COOR¹⁴, or SO₂R¹⁴.
 22. The compound of claim 20,wherein each R⁴ is independently C(O)R¹⁴, C(S)R¹⁴, COOR¹⁴, C(S)OR¹⁴,C(O)NR¹⁴R¹⁵, C(S)NR¹⁴R¹⁵, SO₂R¹⁴, or SO₂NR¹⁴R¹⁵; each R^(4a) and eachR^(4b) is independently selected from hydrogen, OR¹⁴, NR¹⁴R¹⁵,C(O)NR¹⁴R¹⁵, NR¹¹C(O)R¹⁴, NR¹¹C(O)NHSO₂R¹⁴, NR¹¹C(O)NR¹⁴R¹⁵, OC(O)R¹⁴,OC(O)NR¹⁴R¹⁵, OC(O)NHSO₂R¹⁴, HetCy, (C₁-C₃)alkyl, or (C₁-C₃)alkylsubstituted with NR¹⁴R¹⁵, COOR¹⁴, C(O)NHSO₂R¹⁴, or C(O)NR¹⁴R¹⁵; and eachR⁵ is independently hydrogen, halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,hydroxy, C(O)OH, C(O)O(C₁-C₃)alkyl, C(O)NH₂, C(O)NH(C₁-C₃)alkyl,C(O)N((C₁-C₃)alkyl)₂, (C₁-C₃)alkylamino, di(C₁-C₃)alkylamino, NO₂, CN,(C₁-C₃)haloakyl or (C₁-C₃)haloalkoxy.
 23. The compound of claim 22,wherein R¹⁴ is hydrogen and R¹⁵ is independently hydrogen, (C₁-C₃)alkyl,hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, (C₁-C₃)alkylamino(C₁-C₃)alkyl,or di-(C₁-C₃)alkylamino(C₁-C₃)alkyl; or NR¹⁴R¹⁵ taken together forms a5- or 6-membered heterocyclic group containing 1 or 2 nitrogen atoms, 0or 1 oxygen atoms and 0 or 1 sulfur atoms, said ring being optionallysubstituted at any one or more substitutable ring carbon with oxo,hydroxy, or (C₁-C₃)alkyl, and optionally substituted at any one or moresubstitutable ring nitrogen with (C₁-C₃)alkyl, C(O)R¹¹, C(O)OR¹¹ orC(O)NR¹¹R¹².
 24. A pharmaceutical composition comprising an effectiveamount of a compound according to claim 1, and a pharmaceuticallyacceptable carrier or diluent.
 25. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 26. A method of treatinga subject with a disease selected from diabetes mellitus, metabolicsyndrome, glucose intolerance, hyperglycemia, cognitive decline,hypertension, hyperlipidemia, insulin resistance, and hypertensioncaused by cardiovascular disease, comprising the step of administeringto the subject an effective amount of the compound in claim
 1. 27. Themethod of claim 26, wherein the disease is Type II diabetes mellitus.